Is CFHR2 p.Cys72Tyr (c.215G>A) pathogenic?

CFHR2 p.Cys72Tyr (c.215G>A) is classified Benign/Likely benign in CFHR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.9267); Common (popmax 8.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFHR2 p.Cys72Tyr (c.215G>A)?

CFHR2 p.Cys72Tyr (c.215G>A) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CFHR2 p.Cys72Tyr (c.215G>A)?

AlphaMissense predicts likely pathogenic (score 0.9267) — an in-silico prediction, not a clinical call.

CFHR2 p.Cys72Tyr

Q: How common is CFHR2 p.Cys72Tyr (c.215G>A) in the general population?

CFHR2 p.Cys72Tyr (c.215G>A) is common (popmax 8.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.215G>A · rs79351096 · VCV1712442

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9267 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.1%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.9267	likely pathogenic · top 4% in CFHR2
REVEL	0.422	indeterminate
SaProt	LLR -14.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 15 kb · p 0.97 · regional, not allelic
Overall
CADD	21.9	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 8.1% Admixed American · 4,857/59,966 alleles

Filtering AF 7.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.83%

Overall 2.51% 40,549/1,613,888 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	16.3%	6
Admixed Americangrpmax	8.1%	12
South Asian	3.06%	33
Finnishnot grpmax-eligible	2.83%	35
European (non-Finnish)	2.45%	41
Remaining individualsnot grpmax-eligible	2.04%	49
Ashkenazi Jewishnot grpmax-eligible	1.23%	81
Middle Eastern	0.644%	155
African / African-American	0.449%	223
East Asian	0.0111%	8,974

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys72Tyr
Coding: c.215G>A
MANE Select: NM_005666
dbSNP: rs79351096
Type: single nucleotide variant
Location: chr1:196949611 (GRCh38)
Gene constraint: LOEUF 1.498 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.90 · 4 PDB
Residue 72: the sushi 1 domain; a disulfide bond

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

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

CFHR2 p.Thr71= Benign ★★ same condition
CFHR2 p.Thr71Met Likely benign ★★ same condition
CFHR2 p.Tyr264Cys Likely benign ★★ ⚠ same condition
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

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-cys72tyr (accessed [today's date]).

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