Is CFHR3 p.Cys268Phe (c.803G>T) pathogenic?

CFHR3 p.Cys268Phe (c.803G>T) is classified Likely benign in CFHR3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-23). AlphaMissense: likely pathogenic (0.9465); Ultra-rare (popmax 0.0716%, sas); Associated with age related macular degeneration 1.

What condition is associated with CFHR3 p.Cys268Phe (c.803G>T)?

CFHR3 p.Cys268Phe (c.803G>T) is associated with age related macular degeneration 1 (ClinVar).

How common is CFHR3 p.Cys268Phe (c.803G>T) in the general population?

CFHR3 p.Cys268Phe (c.803G>T) is ultra-rare (popmax 0.0716%, sas) (gnomAD).

What do computational predictors say about CFHR3 p.Cys268Phe (c.803G>T)?

AlphaMissense predicts likely pathogenic (score 0.9465) — an in-silico prediction, not a clinical call.

CFHR3 p.Cys268Phe

c.803G>T · rs745503234 · VCV523008

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9465 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0716%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 1

Computational evidence

Protein change
AlphaMissense	0.9465	likely pathogenic · top 5% in CFHR3
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -15.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.95	unconstrained · MANE · 3,283 bp · p 0.67 · regional, not allelic
Overall
CADD	21.7	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 0.0716% South Asian · 57/79,596 alleles

Filtering AF 0.0567% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.00484% 73/1,509,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0716%	1,396
Middle Eastern	0.0191%	5,238
East Asian	0.00678%	14,744
Remaining individualsnot grpmax-eligible	0.00345%	28,999
European (non-Finnish)	0.000896%	111,665

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: CFHR3
Protein: p.Cys268Phe
Coding: c.803G>T
MANE Select: NM_021023
dbSNP: rs745503234
Type: single nucleotide variant
Location: chr1:196793323 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 268: a disulfide bond; the sushi 5 domain

Full CFHR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

age related macular degeneration 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR3 p.Arg142Cys Benign ★★ ⚠ same condition
CFHR3 p.Gln240His Benign ★★ ⚠ same condition
CFHR3 p.Ile269Val Likely benign ★★ same condition
CFHR3 p.Ile312Phe Benign/Likely benign ★★ same condition
CFHR3 p.Phe34Cys Benign/Likely benign ★★ ⚠ same condition
CFHR3 p.Gly178= Uncertain significance ★ same condition
CFHR3 p.Ile280fs Uncertain significance ★★ same condition
CFHR3 p.Phe34fs Uncertain significance ★ same condition

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/cfhr3-p-cys268phe (accessed [today's date]).

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