Is MSH6 p.Pro44Leu (c.131C>T) pathogenic?

MSH6 p.Pro44Leu (c.131C>T) is classified Conflicting classifications of pathogenicity in MSH6 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1102); Very rare (popmax 0.000425%, nfe); Associated with mismatch repair cancer syndrome 3.

What condition is associated with MSH6 p.Pro44Leu (c.131C>T)?

MSH6 p.Pro44Leu (c.131C>T) is associated with mismatch repair cancer syndrome 3, endometrial carcinoma, Lynch syndrome (ClinVar).

How common is MSH6 p.Pro44Leu (c.131C>T) in the general population?

MSH6 p.Pro44Leu (c.131C>T) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about MSH6 p.Pro44Leu (c.131C>T)?

AlphaMissense predicts likely benign (score 0.1102) — an in-silico prediction, not a clinical call.

MSH6 p.Pro44Leu

Q: How is Constitutional mismatch repair deficiency syndrome inherited?

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

c.131C>T · rs863224615 · VCV216295

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mismatch repair cancer syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1102	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.088	GERP -1.1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	17.86	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 0.000425% European (non-Finnish) · 5/1,176,158 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000312% 5/1,604,884 alleles · very rare exomes 4/1,452,692 · genomes 1/152,192 · 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: MSH6
Protein: p.Pro44Leu
Coding: c.131C>T
MANE Select: NM_000179
dbSNP: rs863224615
Type: single nucleotide variant
Location: chr2:47783364 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 44: the 'disordered' region

Full MSH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mismatch repair cancer syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma Lynch syndrome Lynch syndrome 5 hereditary neoplastic syndrome

For Constitutional mismatch repair deficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MSH6 p.Pro44Gln Uncertain significance ★ ⚠ same residue
MSH6 p.Pro44Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro44fs Pathogenic ★ same residue
MSH6 p.Pro44Ala Uncertain significance ★ ⚠ same residue
MSH6 p.Pro44Thr Uncertain significance ★ ⚠ same residue
MSH6 p.Pro44= Likely benign ★ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+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/msh6-p-pro44leu (accessed [today's date]).

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