Is MSH6 p.Arg554Pro (c.1661G>C) pathogenic?

MSH6 p.Arg554Pro (c.1661G>C) is classified Uncertain significance in MSH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: likely pathogenic (0.6125); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Arg554Pro (c.1661G>C)?

MSH6 p.Arg554Pro (c.1661G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Arg554Pro (c.1661G>C) in the general population?

MSH6 p.Arg554Pro (c.1661G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH6 p.Arg554Pro (c.1661G>C)?

AlphaMissense predicts likely pathogenic (score 0.6125) — an in-silico prediction, not a clinical call.

MSH6 p.Arg554Pro

c.1661G>C · VCV3875102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6125 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6125	likely pathogenic
REVEL	0.594	indeterminate
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP -0.66, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	21.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH6
Protein: p.Arg554Pro
Coding: c.1661G>C
MANE Select: NM_000179
Type: single nucleotide variant
Location: chr2:47799644 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 554: a β-strand

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

Similar variants

MSH6 p.Arg554= Benign/Likely benign ★★ same residue
MSH6 p.Arg554Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Arg554Gly Uncertain significance ★ ⚠ same residue
MSH6 p.Arg554His Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Arg554Ser 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

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-arg554pro (accessed [today's date]).

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