Is RFC2 p.Arg91Trp (c.271C>T) pathogenic?

RFC2 p.Arg91Trp (c.271C>T) is classified Uncertain significance in RFC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: ambiguous (0.4489); Very rare (popmax 0.00801%, afr).

How common is RFC2 p.Arg91Trp (c.271C>T) in the general population?

RFC2 p.Arg91Trp (c.271C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about RFC2 p.Arg91Trp (c.271C>T)?

AlphaMissense predicts ambiguous (score 0.4489) — an in-silico prediction, not a clinical call.

RFC2 p.Arg91Trp

c.271C>T · VCV3944877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4489	ambiguous
REVEL	0.725	pathogenic-leaning
SaProt	LLR -17.40	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 4.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 22 kb · p 0.012 · regional, not allelic
Overall
CADD	26.2	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 0.00801% African / African-American · 6/74,936 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00285% 46/1,613,966 alleles · very rare exomes 37/1,461,778 · genomes 9/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,489
South Asian	0.00329%	30,361
European (non-Finnish)	0.00305%	32,778
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: RFC2
Protein: p.Arg91Trp
Coding: c.271C>T
MANE Select: NM_181471
Type: single nucleotide variant
Location: chr7:74249073 (GRCh38)
Gene constraint: LOEUF 1.394 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 16 PDB
Residue 91: an α-helix

Full RFC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RFC2 p.Ala196Thr Uncertain significance ★★ ⚠ same type
RFC2 c.759+8C>T Benign ★★ same type
RFC2 p.Ala232Val Likely benign ★★ same type
RFC2 p.Arg201= Benign ★★ same type
RFC2 p.His33= Benign ★★ same type
RFC2 p.Thr129= Benign ★★ same type
RFC2 p.Ala150Val Uncertain significance ★ ⚠ same type
RFC2 p.Ala15Val 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/rfc2-p-arg91trp (accessed [today's date]).

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