Is RFC4 p.Ala342Val (c.1025C>T) pathogenic?

RFC4 p.Ala342Val (c.1025C>T) is classified Uncertain significance in RFC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). AlphaMissense: likely pathogenic (0.8238); Ultra-rare (popmax 0.033%, mid).

How common is RFC4 p.Ala342Val (c.1025C>T) in the general population?

RFC4 p.Ala342Val (c.1025C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about RFC4 p.Ala342Val (c.1025C>T)?

AlphaMissense predicts likely pathogenic (score 0.8238) — an in-silico prediction, not a clinical call.

RFC4 p.Ala342Val

c.1025C>T · VCV3313854

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8238 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8238	likely pathogenic
REVEL	0.306	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.92, phastCons 1
Regional constraint	o/e 1.61	unconstrained · MANE · 2,554 bp · p 8.7e-16 · regional, not allelic
Overall
CADD	24.4	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000137% 2/1,461,294 alleles · ultra-rare

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: RFC4
Protein: p.Ala342Val
Coding: c.1025C>T
MANE Select: NM_002916
Type: single nucleotide variant
Location: chr3:186790036 (GRCh38)
Gene constraint: LOEUF 1.096 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 16 PDB

Full RFC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RFC4 c.996+9G>A Benign ★★ same type
RFC4 c.290+5G>T Likely pathogenic ★ same type
RFC4 p.Ala271Val Uncertain significance ★ ⚠ same type
RFC4 p.Ala279Pro Uncertain significance ★ ⚠ same type
RFC4 p.Ala279Thr Uncertain significance ★ ⚠ same type
RFC4 p.Ala339Glu Uncertain significance ★ ⚠ same type
RFC4 p.Ala339Val Uncertain significance ★ ⚠ same type
RFC4 p.Ala3Thr Uncertain significance ★ ⚠ same type

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/rfc4-p-ala342val (accessed [today's date]).

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