Is MSH4 p.Pro345Ala (c.1033C>G) pathogenic?

MSH4 p.Pro345Ala (c.1033C>G) is classified Uncertain significance in MSH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0509); Very rare (popmax 0.00938%, sas); Associated with Inborn genetic diseases.

What condition is associated with MSH4 p.Pro345Ala (c.1033C>G)?

MSH4 p.Pro345Ala (c.1033C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MSH4 p.Pro345Ala (c.1033C>G) in the general population?

MSH4 p.Pro345Ala (c.1033C>G) is very rare (popmax 0.00938%, sas) (gnomAD).

What do computational predictors say about MSH4 p.Pro345Ala (c.1033C>G)?

AlphaMissense predicts likely benign (score 0.0509) — an in-silico prediction, not a clinical call.

MSH4 p.Pro345Ala

c.1033C>G · rs573895131 · VCV2243869

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00938%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0509	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -5.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 116 kb · p 0.32 · regional, not allelic
Overall
CADD	17.87	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 0.00938% South Asian · 8/85,248 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00341%

Overall 0.000569% 9/1,582,512 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00938%	10,656
Remaining individualsnot grpmax-eligible	0.00163%	61,260

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: MSH4
Protein: p.Pro345Ala
Coding: c.1033C>G
MANE Select: NM_002440
dbSNP: rs573895131
Type: single nucleotide variant
Location: chr1:75822452 (GRCh38)
Gene constraint: LOEUF 1.19 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.12

Full MSH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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MSH4 p.Ala148Val Uncertain significance ★ ⚠ same condition
MSH4 p.Ala195Thr Uncertain significance ★ ⚠ same condition
MSH4 p.Ala310Val Uncertain significance ★ ⚠ same condition
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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/msh4-p-pro345ala (accessed [today's date]).

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