Is CFHR4 p.Asp258Glu (c.774C>G) pathogenic?

CFHR4 p.Asp258Glu (c.774C>G) is classified Benign/Likely benign in CFHR4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.0752); Low-frequency (popmax 2.95%, afr).

How common is CFHR4 p.Asp258Glu (c.774C>G) in the general population?

CFHR4 p.Asp258Glu (c.774C>G) is low-frequency (popmax 2.95%, afr) (gnomAD).

What do computational predictors say about CFHR4 p.Asp258Glu (c.774C>G)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

CFHR4 p.Asp258Glu

c.774C>G · rs144216823 · VCV1336124

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.95%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -1.67	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 -0.27	GERP -1.7
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	0.036	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 2.95% African / African-American · 2,192/74,266 alleles

Filtering AF 2.85% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.81%

Overall 0.153% 2,465/1,611,134 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.95%	34
Remaining individualsnot grpmax-eligible	0.218%	459
Admixed American	0.194%	515
Middle Eastern	0.0661%	1,514
South Asian	0.0066%	15,157
European (non-Finnish)	0.000933%	107,150

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.Asp258Glu
Coding: c.774C>G
MANE Select: NM_001201550
dbSNP: rs144216823
Type: single nucleotide variant
Location: chr1:196907473 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 258: a disulfide bond; the sushi 4 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-asp258glu (accessed [today's date]).

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