Is MLH1 p.Ala92Val (c.275C>T) pathogenic?

MLH1 p.Ala92Val (c.275C>T) is classified Uncertain significance in MLH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-11). AlphaMissense: likely benign (0.1419); Very rare (popmax 0.00167%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MLH1 p.Ala92Val (c.275C>T) in the general population?

MLH1 p.Ala92Val (c.275C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MLH1 p.Ala92Val (c.275C>T)?

AlphaMissense predicts likely benign (score 0.1419) — an in-silico prediction, not a clinical call.

MLH1 p.Ala92Val

Q: What condition is associated with MLH1 p.Ala92Val (c.275C>T)?

MLH1 p.Ala92Val (c.275C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.275C>T · rs768132746 · VCV1055509

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1419 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1419	likely benign
REVEL	0.64	indeterminate
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.21	donor loss, 26 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 57 kb · p 0.11 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,992 alleles

Overall 6.21e-05% 1/1,610,790 alleles · very rare exomes 0/1,458,750 · genomes 1/152,040 · joint denominator

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.Ala92Val
Coding: c.275C>T
MANE Select: NM_000249
dbSNP: rs768132746
Type: single nucleotide variant
Location: chr3:37001022 (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

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

Also linked: hereditary neoplastic syndrome

Similar variants

MLH1 p.Ala92= Benign/Likely benign ★★ same residue
MLH1 p.Ala92Thr Uncertain significance ★ ⚠ same residue
MLH1 c.1039-1G>A 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
MLH1 c.117-1G>T Likely pathogenic ★★★ same condition
MLH1 c.117-2A>G 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-ala92val (accessed [today's date]).

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