Is CFHR4 p.Tyr205His (c.613T>C) pathogenic?

CFHR4 p.Tyr205His (c.613T>C) is classified Conflicting classifications of pathogenicity in CFHR4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-25). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.0311%, afr).

How common is CFHR4 p.Tyr205His (c.613T>C) in the general population?

CFHR4 p.Tyr205His (c.613T>C) is ultra-rare (popmax 0.0311%, afr) (gnomAD).

What do computational predictors say about CFHR4 p.Tyr205His (c.613T>C)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

CFHR4 p.Tyr205His

c.613T>C · VCV3266601

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0311%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.3	GERP 0.4
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	16.95	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 0.0311% African / African-American · 23/74,022 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00193% 31/1,606,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0311%	3,218
Remaining individualsnot grpmax-eligible	0.00965%	10,362
Admixed American	0.0017%	58,950
European (non-Finnish)	8.5e-05%	1,176,216

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.Tyr205His
Coding: c.613T>C
MANE Select: NM_001201550
Type: single nucleotide variant
Location: chr1:196907034 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 205: the sushi 3 domain

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

Similar variants

CFHR4 p.Tyr205Cys 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.Ser507Leu Uncertain significance ★★ ⚠ same type
CFHR4 p.Trp68Ter Uncertain significance ★★ same type
CFHR4 p.Tyr238Ser 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/cfhr4-p-tyr205his (accessed [today's date]).

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