Is MLH1 p.Pro355Ser (c.1063C>T) pathogenic?

MLH1 p.Pro355Ser (c.1063C>T) is classified Conflicting classifications of pathogenicity in MLH1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.0652); Very rare (popmax 0.00272%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Pro355Ser (c.1063C>T)?

MLH1 p.Pro355Ser (c.1063C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 2 (ClinVar).

How common is MLH1 p.Pro355Ser (c.1063C>T) in the general population?

MLH1 p.Pro355Ser (c.1063C>T) is very rare (popmax 0.00272%, sas) (gnomAD).

What do computational predictors say about MLH1 p.Pro355Ser (c.1063C>T)?

AlphaMissense predicts likely benign (score 0.0652) — an in-silico prediction, not a clinical call.

MLH1 p.Pro355Ser

c.1063C>T · rs756347993 · VCV237308

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0652	likely benign
REVEL	0.482	indeterminate
SaProt	LLR -5.50	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 0.23	GERP -1.1, phastCons 0.02
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	13.84	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 0.00272% South Asian · 2/73,590 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000197% 3/1,525,150 alleles · very rare exomes 2/1,380,516 · genomes 1/144,634 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00272%	36,795
African / African-American	0.00144%	69,546

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.Pro355Ser
Coding: c.1063C>T
MANE Select: NM_000249
dbSNP: rs756347993
Type: single nucleotide variant
Location: chr3:37025661 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 355: the 'disordered' region

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

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 2 hereditary neoplastic syndrome

Similar variants

MLH1 p.Pro355Ala Uncertain significance ★★ ⚠ same residue
MLH1 p.Pro355= Likely benign ★★ same residue
MLH1 p.Pro355Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro355ser (accessed [today's date]).

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