Is RFC3 p.Ser2Arg (c.6C>G) pathogenic?

RFC3 p.Ser2Arg (c.6C>G) is classified Uncertain significance in RFC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely pathogenic (0.9755); Ultra-rare (popmax 0.028%, afr).

How common is RFC3 p.Ser2Arg (c.6C>G) in the general population?

RFC3 p.Ser2Arg (c.6C>G) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about RFC3 p.Ser2Arg (c.6C>G)?

AlphaMissense predicts likely pathogenic (score 0.9755) — an in-silico prediction, not a clinical call.

RFC3 p.Ser2Arg

c.6C>G · rs147166048 · VCV3153353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9755	likely pathogenic
REVEL	0.368	indeterminate
SaProt	LLR -11.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -3.1, phastCons 0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 18 kb · p 0.81 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.028% African / African-American · 21/74,920 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00136% 22/1,613,082 alleles · ultra-rare exomes 10/1,460,820 · genomes 12/152,262 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,568
Remaining individualsnot grpmax-eligible	0.0016%	62,452

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: RFC3
Protein: p.Ser2Arg
Coding: c.6C>G
MANE Select: NM_002915
dbSNP: rs147166048
Type: single nucleotide variant
Location: chr13:33818184 (GRCh38)
Gene constraint: LOEUF 1.153 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.58 · 16 PDB

Full RFC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RFC3 p.Ser2Ile Uncertain significance ★ ⚠ same residue
RFC3 p.Ala181Val Uncertain significance ★ ⚠ same type
RFC3 p.Ala186Thr Uncertain significance ★ ⚠ same type
RFC3 p.Ala334Val Uncertain significance ★ ⚠ same type
RFC3 p.Arg15Pro Uncertain significance ★ ⚠ same type
RFC3 p.Arg321Cys Uncertain significance ★ same type
RFC3 p.Arg57Cys Uncertain significance ★ ⚠ same type
RFC3 p.Asn206Thr 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/rfc3-p-ser2arg (accessed [today's date]).

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