Is RFC4 p.Pro15Arg (c.44C>G) pathogenic?

RFC4 p.Pro15Arg (c.44C>G) is classified Uncertain significance in RFC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). AlphaMissense: likely benign (0.0821); Very rare (popmax 0.00534%, afr).

How common is RFC4 p.Pro15Arg (c.44C>G) in the general population?

RFC4 p.Pro15Arg (c.44C>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about RFC4 p.Pro15Arg (c.44C>G)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

RFC4 p.Pro15Arg

c.44C>G · rs146612878 · VCV2612507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0821	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -8.11	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 3	GERP 0.91, phastCons 0.89
Regional constraint	o/e 0.80	unconstrained · MANE · 12 kb · p 0.0013 · regional, not allelic
Overall
CADD	7.245	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 0.00534% African / African-American · 4/74,868 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,613,880 alleles · very rare exomes 2/1,461,804 · genomes 2/152,076 · 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: RFC4
Protein: p.Pro15Arg
Coding: c.44C>G
MANE Select: NM_002916
dbSNP: rs146612878
Type: single nucleotide variant
Location: chr3:186804670 (GRCh38)
Gene constraint: LOEUF 1.096 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 16 PDB
Residue 15: the 'disordered' region

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

Similar variants

RFC4 p.Pro15Ser Uncertain significance ★ ⚠ same residue
RFC4 p.Pro15Leu Likely benign ★ same residue
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

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-pro15arg (accessed [today's date]).

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