Is CFHR4 p.Val21Ala (c.62T>C) pathogenic?

CFHR4 p.Val21Ala (c.62T>C) is classified Benign/Likely benign in CFHR4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.157); Low-frequency (popmax 2.42%, afr).

How common is CFHR4 p.Val21Ala (c.62T>C) in the general population?

CFHR4 p.Val21Ala (c.62T>C) is low-frequency (popmax 2.42%, afr) (gnomAD).

What do computational predictors say about CFHR4 p.Val21Ala (c.62T>C)?

AlphaMissense predicts likely benign (score 0.157) — an in-silico prediction, not a clinical call.

CFHR4 p.Val21Ala

c.62T>C · rs78624607 · VCV1336292

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.157 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.42%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.157	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	acceptor loss · deltas
Constraint at this position
Conservation	phyloP -10	GERP -0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	14.47	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 2.42% African / African-American · 1,786/73,788 alleles

Filtering AF 2.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.29%

Overall 0.124% 1,981/1,601,254 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.42%	41
Remaining individualsnot grpmax-eligible	0.171%	585
Admixed American	0.122%	820
Middle Eastern	0.0664%	1,505
South Asian	0.00336%	29,799
European (non-Finnish)	0.000853%	117,244

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.Val21Ala
Coding: c.62T>C
MANE Select: NM_001201550
dbSNP: rs78624607
Type: single nucleotide variant
Location: chr1:196902421 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 21: the sushi 1 domain

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

Similar variants

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.Ser507Leu 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-val21ala (accessed [today's date]).

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