Is MLH1 p.Ser692Pro (c.2074T>C) pathogenic?

MLH1 p.Ser692Pro (c.2074T>C) is classified Benign in MLH1 (ClinVar, Expert panel, 7 submitters; last evaluated 2018-06-13). AlphaMissense: likely benign (0.075); Very rare (popmax 0.0011%, nfe); Associated with Lynch syndrome 1.

What condition is associated with MLH1 p.Ser692Pro (c.2074T>C)?

MLH1 p.Ser692Pro (c.2074T>C) is associated with Lynch syndrome 1, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Ser692Pro (c.2074T>C) in the general population?

MLH1 p.Ser692Pro (c.2074T>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MLH1 p.Ser692Pro (c.2074T>C)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

MLH1 p.Ser692Pro

c.2074T>C · rs587779957 · VCV127621

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lynch syndrome 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Likely Benign for Lynch syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting BS4 BP4

Curation rationale (ClinGen, verbatim)

The MLH1 c.2074T>C variant is predicted as a missense variant, p.(Ser692Pro). Its MAPP+PolyPhen-2 prior probability for pathogenicity is <0.11 (http://priors.hci.utah.edu/PRIORS). It is extremely rare (<1 in 50,000 alleles:0,002%) in gnomAD v2.1.1. non-cancer dataset and gnomAD v4.1. It showed lack of co-segregation with disease with a Bayes likelihood ratio <0.05 (Mayo CCFR). Therefore, this variant is classified as likely benign. (VCEP specifications version 1)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -4.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.31	GERP 1.1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	14.68	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,936 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000867% 14/1,614,066 alleles · very rare exomes 14/1,461,768 · genomes 0/152,298 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	0.0011%	90,765

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MLH1
Protein: p.Ser692Pro
Coding: c.2074T>C
MANE Select: NM_000249
dbSNP: rs587779957
Type: single nucleotide variant
Location: chr3:37048988 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB

Full MLH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Ser692= Likely benign ★★ same residue
MLH1 p.Ser692fs Pathogenic ★ same residue
MLH1 c.1038+1G>C Likely pathogenic ★★★ same condition
MLH1 c.1039-1G>A Pathogenic ★★★ same condition
MLH1 c.1039-2A>G Likely pathogenic ★★★ same condition
MLH1 c.1039-2A>T Likely pathogenic ★★★ same condition
MLH1 c.116+1G>A Likely pathogenic ★★★ same condition
MLH1 c.116+5G>C Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mlh1-p-ser692pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown