Is CFHR2 p.Ala73Thr (c.217G>A) pathogenic?

CFHR2 p.Ala73Thr (c.217G>A) is classified Conflicting classifications of pathogenicity in CFHR2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-23). AlphaMissense: likely benign (0.0523); Rare (popmax 0.101%, afr).

How common is CFHR2 p.Ala73Thr (c.217G>A) in the general population?

CFHR2 p.Ala73Thr (c.217G>A) is rare (popmax 0.101%, afr) (gnomAD).

What do computational predictors say about CFHR2 p.Ala73Thr (c.217G>A)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

CFHR2 p.Ala73Thr

c.217G>A · rs372833461 · VCV2370593

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.101%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -1.79	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 1.6	GERP 0.44, phastCons 0.001
Regional constraint	o/e 1.00	unconstrained · MANE · 15 kb · p 0.97 · regional, not allelic
Overall
CADD	5.032	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 0.101% African / African-American · 76/74,986 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0762%

Overall 0.0317% 512/1,613,890 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.101%	987
Remaining individualsnot grpmax-eligible	0.0416%	2,404
European (non-Finnish)	0.0333%	3,002
Admixed American	0.0233%	4,284
South Asian	0.0022%	45,544
Finnishnot grpmax-eligible	0.00156%	64,024

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: CFHR2
Protein: p.Ala73Thr
Coding: c.217G>A
MANE Select: NM_005666
dbSNP: rs372833461
Type: single nucleotide variant
Location: chr1:196949613 (GRCh38)
Gene constraint: LOEUF 1.498 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.90 · 4 PDB
Residue 73: the sushi 1 domain; a disulfide bond

Full CFHR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR2 p.Val16Ala Uncertain significance ★★ ⚠ same type
CFHR2 c.430+141T>A Benign ★★ same type
CFHR2 c.430+20C>T Benign ★★ same type
CFHR2 c.430+7G>A Benign/Likely benign ★★ same type
CFHR2 c.431-48C>A Benign ★★ same type
CFHR2 c.431-65C>T Benign ★★ same type
CFHR2 c.58+129C>G Benign ★★ same type
CFHR2 c.-65C>G 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/cfhr2-p-ala73thr (accessed [today's date]).

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