Is CFHR3 p.Ser217Cys (c.649A>T) pathogenic?

CFHR3 p.Ser217Cys (c.649A>T) is classified Uncertain significance in CFHR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: ambiguous (0.3744); Very rare (popmax 0.000294%, nfe).

How common is CFHR3 p.Ser217Cys (c.649A>T) in the general population?

CFHR3 p.Ser217Cys (c.649A>T) is very rare (popmax 0.000294%, nfe) (gnomAD).

What do computational predictors say about CFHR3 p.Ser217Cys (c.649A>T)?

AlphaMissense predicts ambiguous (score 0.3744) — an in-silico prediction, not a clinical call.

CFHR3 p.Ser217Cys

c.649A>T · VCV4001748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000294%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3744	ambiguous
REVEL	0.217	benign-leaning
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1	GERP -3.6
Regional constraint	o/e 0.30	constrained · MANE · 169 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	18.44	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 0.000294% European (non-Finnish) · 3/1,021,218 alleles

Filtering AF 7.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2e-05%

Overall 0.000241% 3/1,247,252 alleles · very rare

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.Ser217Cys
Coding: c.649A>T
MANE Select: NM_021023
Type: single nucleotide variant
Location: chr1:196790080 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 217: a disulfide bond; the sushi 4 domain

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

Similar variants

CFHR3 p.Ser217Arg Uncertain significance ★ ⚠ same residue
CFHR3 p.Ser217Gly Uncertain significance ★ ⚠ same residue
CFHR3 c.796+1G>A Uncertain significance ★★ same type
CFHR3 p.Arg320Gln Uncertain significance ★★ ⚠ same type
CFHR3 p.Gly119Ala Uncertain significance ★★ ⚠ same type
CFHR3 p.Ile70Thr Uncertain significance ★★ ⚠ same type
CFHR3 p.Tyr118Ter Uncertain significance ★★ same type
CFHR3 c.431-88C>T 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/cfhr3-p-ser217cys (accessed [today's date]).

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