Is RFC4 p.Leu289Val (c.865C>G) pathogenic?

RFC4 p.Leu289Val (c.865C>G) is classified Uncertain significance in RFC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely benign (0.1081); Ultra-rare (popmax 0.0178%, eas).

How common is RFC4 p.Leu289Val (c.865C>G) in the general population?

RFC4 p.Leu289Val (c.865C>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about RFC4 p.Leu289Val (c.865C>G)?

AlphaMissense predicts likely benign (score 0.1081) — an in-silico prediction, not a clinical call.

RFC4 p.Leu289Val

c.865C>G · VCV3313853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1081	likely benign
REVEL	0.239	benign-leaning
SaProt	LLR -4.52	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 1.6	GERP -0.23, phastCons 1
Regional constraint	o/e 1.61	unconstrained · MANE · 2,554 bp · p 8.7e-16 · regional, not allelic
Overall
CADD	18.12	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 0.0178% East Asian · 8/44,884 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,613,524 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.Leu289Val
Coding: c.865C>G
MANE Select: NM_002916
Type: single nucleotide variant
Location: chr3:186790343 (GRCh38)
Gene constraint: LOEUF 1.096 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 16 PDB
Residue 289: an α-helix

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.Ala342Val 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-leu289val (accessed [today's date]).

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