Is MSH6 p.Ala16= (c.48G>A) pathogenic?

MSH6 p.Ala16= (c.48G>A) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-16). Very rare (popmax 0.000593%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Ala16= (c.48G>A)?

MSH6 p.Ala16= (c.48G>A) is associated with hereditary neoplastic syndrome, Lynch syndrome 5 (ClinVar).

How common is MSH6 p.Ala16= (c.48G>A) in the general population?

MSH6 p.Ala16= (c.48G>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

MSH6 p.Ala16=

c.48G>A · rs1250671114 · VCV1147441

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1, phastCons 0.12
Overall
CADD	13.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,570 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,612,016 alleles · very rare exomes 5/1,459,830 · genomes 2/152,186 · 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.Ala16=
Coding: c.48G>A
MANE Select: NM_000179
dbSNP: rs1250671114
Type: single nucleotide variant
Location: chr2:47783281 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 16: the 'disordered' region

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

Disease context

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

Also linked: Lynch syndrome 5

Similar variants

MSH6 p.Ala16Glu Uncertain significance ★★ ⚠ same residue
MSH6 p.Ala16Thr Uncertain significance ★★ ⚠ same residue
MSH6 p.Ala16Val Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ala16Ser Uncertain significance ★ ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A Likely pathogenic ★★★ same condition
MSH6 c.3439-1G>T Likely pathogenic ★★★ same condition
MSH6 c.3439-2A>G 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-ala16 (accessed [today's date]).

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