Is CFHR4 p.Ser507Pro (c.1519T>C) pathogenic?

CFHR4 p.Ser507Pro (c.1519T>C) is classified Uncertain significance in CFHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely pathogenic (0.7428); Very rare (popmax 0.00538%, afr).

How common is CFHR4 p.Ser507Pro (c.1519T>C) in the general population?

CFHR4 p.Ser507Pro (c.1519T>C) is very rare (popmax 0.00538%, afr) (gnomAD).

What do computational predictors say about CFHR4 p.Ser507Pro (c.1519T>C)?

AlphaMissense predicts likely pathogenic (score 0.7428) — an in-silico prediction, not a clinical call.

CFHR4 p.Ser507Pro

c.1519T>C · VCV4001757

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7428 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00538%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7428	likely pathogenic
REVEL	0.394	indeterminate
SaProt	LLR -11.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP 0.56, phastCons 0.17
Regional constraint	o/e 0.30	constrained · MANE · 182 bp · p 2.6e-09 · regional, not allelic
Overall
CADD	21.0	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 0.00538% African / African-American · 4/74,300 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00031% 5/1,612,538 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00538%	18,575
European (non-Finnish)	8.48e-05%	1,179,668

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: CFHR4
Protein: p.Ser507Pro
Coding: c.1519T>C
MANE Select: NM_001201550
Type: single nucleotide variant
Location: chr1:196915117 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 507: a disulfide bond; the sushi 8 domain

Full CFHR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR4 p.Ser507Leu Uncertain significance ★★ ⚠ same residue
CFHR4 p.Ala159Val Uncertain significance ★★ ⚠ same type
CFHR4 p.Arg40His Uncertain significance ★★ ⚠ same type
CFHR4 p.Ile318Thr Uncertain significance ★★ ⚠ same type
CFHR4 p.Ser199Tyr Uncertain significance ★★ ⚠ same type
CFHR4 p.Trp68Ter Uncertain significance ★★ same type
CFHR4 p.Tyr238Ser Uncertain significance ★★ ⚠ same type
CFHR4 c.1180+4A>C Benign/Likely benign ★★ 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/cfhr4-p-ser507pro (accessed [today's date]).

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