Is CFHR3 p.Ser159= (c.477C>T) pathogenic?

CFHR3 p.Ser159= (c.477C>T) is classified Benign/Likely benign in CFHR3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-26). Common (popmax 93.5%, eas) — too common for a highly-penetrant pathogenic allele.

CFHR3 p.Ser159=

Q: How common is CFHR3 p.Ser159= (c.477C>T) in the general population?

CFHR3 p.Ser159= (c.477C>T) is common (popmax 93.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.477C>T · rs400344 · VCV1244350

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 93.5%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -3.6, phastCons 0.99
Overall
CADD	11.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 93.5% East Asian · 38,736/41,436 alleles

Filtering AF 92.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 92.4%

Overall 45.1% 534,639/1,185,514 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	93.5%	1
Admixed American	71.6%	1
African / African-American	69.8%	1
South Asian	48%	2
Ashkenazi Jewishnot grpmax-eligible	47.9%	2
Remaining individualsnot grpmax-eligible	47.1%	2
Finnishnot grpmax-eligible	45.2%	2
Amishnot grpmax-eligible	43.6%	2
European (non-Finnish)	39.7%	3
Middle Eastern	36.6%	3

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.Ser159=
Coding: c.477C>T
MANE Select: NM_021023
dbSNP: rs400344
Type: single nucleotide variant
Location: chr1:196788262 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 159: a disulfide bond; the sushi 3 domain

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

Similar variants

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
CFHR3 c.58+8A>G Likely benign ★★ same type
CFHR3 c.796+22T>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/cfhr3-p-ser159 (accessed [today's date]).

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