Is RFC3 p.Ser2Ile (c.5G>T) pathogenic?

RFC3 p.Ser2Ile (c.5G>T) is classified Uncertain significance in RFC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely pathogenic (0.8346); Ultra-rare (popmax 0.02%, amr).

How common is RFC3 p.Ser2Ile (c.5G>T) in the general population?

RFC3 p.Ser2Ile (c.5G>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about RFC3 p.Ser2Ile (c.5G>T)?

AlphaMissense predicts likely pathogenic (score 0.8346) — an in-silico prediction, not a clinical call.

RFC3 p.Ser2Ile

c.5G>T · VCV3313846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8346 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8346	likely pathogenic
REVEL	0.407	indeterminate
SaProt	LLR -11.98	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 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 18 kb · p 0.81 · regional, not allelic
Overall
CADD	27.4	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 0.02% Admixed American · 12/59,934 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00899%

Overall 0.00112% 18/1,613,188 alleles · ultra-rare exomes 18/1,460,804 · genomes 0/152,384 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,995
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,236
South Asian	0.0022%	45,499
European (non-Finnish)	8.48e-05%	1,179,752

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.Ser2Ile
Coding: c.5G>T
MANE Select: NM_002915
Type: single nucleotide variant
Location: chr13:33818183 (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.Ser2Arg 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-ser2ile (accessed [today's date]).

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