Is RFC5 p.Phe145Ser (c.434T>C) pathogenic?

RFC5 p.Phe145Ser (c.434T>C) is classified Uncertain significance in RFC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.9433); Absent from gnomAD v4.1.

How common is RFC5 p.Phe145Ser (c.434T>C) in the general population?

RFC5 p.Phe145Ser (c.434T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RFC5 p.Phe145Ser (c.434T>C)?

AlphaMissense predicts likely pathogenic (score 0.9433) — an in-silico prediction, not a clinical call.

RFC5 p.Phe145Ser

c.434T>C · VCV4153053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9433 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9433	likely pathogenic
REVEL	0.705	pathogenic-leaning
SaProt	LLR -8.89	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 9.5e-06 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RFC5
Protein: p.Phe145Ser
Coding: c.434T>C
MANE Select: NM_007370
Type: single nucleotide variant
Location: chr12:118024863 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI 0.26 (gnomAD)
Structure: AlphaFold pLDDT 90.52 · 16 PDB
Residue 145: a turn

Full RFC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

WSB2 p.Asp246= Benign ★★ same type
RFC5 p.Ala127Thr Uncertain significance ★ ⚠ same type
RFC5 p.Ala129Thr Uncertain significance ★ ⚠ same type
RFC5 p.Arg173Gln Uncertain significance ★ ⚠ same type
RFC5 p.Arg173Trp Uncertain significance ★ ⚠ same type
RFC5 p.Arg185Cys Uncertain significance ★ ⚠ same type
RFC5 p.Arg185His Uncertain significance ★ same type
RFC5 p.Arg215Ser 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/rfc5-p-phe145ser (accessed [today's date]).

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