Is RFC2 p.Pro22Leu (c.65C>T) pathogenic?

RFC2 p.Pro22Leu (c.65C>T) is classified Uncertain significance in RFC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: likely benign (0.0901); Ultra-rare (popmax 0.0658%, mid).

How common is RFC2 p.Pro22Leu (c.65C>T) in the general population?

RFC2 p.Pro22Leu (c.65C>T) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about RFC2 p.Pro22Leu (c.65C>T)?

AlphaMissense predicts likely benign (score 0.0901) — an in-silico prediction, not a clinical call.

RFC2 p.Pro22Leu

c.65C>T · rs782571058 · VCV2208333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0901 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0901	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -7.77	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 5.4	GERP 5.6, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 22 kb · p 0.012 · regional, not allelic
Overall
CADD	19.01	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 0.0658% Middle Eastern · 4/6,078 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00174% 28/1,612,568 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,520
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,388
Remaining individualsnot grpmax-eligible	0.00642%	15,587
European (non-Finnish)	0.00136%	73,729

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.Pro22Leu
Coding: c.65C>T
MANE Select: NM_181471
dbSNP: rs782571058
Type: single nucleotide variant
Location: chr7:74254319 (GRCh38)
Gene constraint: LOEUF 1.394 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 16 PDB
Residue 22: the 'disordered' region

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-pro22leu (accessed [today's date]).

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