Is CFHR5 p.Ser78Pro (c.232T>C) pathogenic?

CFHR5 p.Ser78Pro (c.232T>C) is classified Conflicting classifications of pathogenicity in CFHR5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.8184); Rare (popmax 0.173%, afr).

How common is CFHR5 p.Ser78Pro (c.232T>C) in the general population?

CFHR5 p.Ser78Pro (c.232T>C) is rare (popmax 0.173%, afr) (gnomAD).

What do computational predictors say about CFHR5 p.Ser78Pro (c.232T>C)?

AlphaMissense predicts likely pathogenic (score 0.8184) — an in-silico prediction, not a clinical call.

CFHR5 p.Ser78Pro

c.232T>C · rs146025130 · VCV732916

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8184 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.173%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8184	likely pathogenic · top 9% in CFHR5
REVEL	0.319	indeterminate
SaProt	LLR -11.74	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 -0.95	GERP -2.4
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	20.4	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 0.173% African / African-American · 130/75,062 alleles

Filtering AF 0.149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.14%

Overall 0.00905% 146/1,614,114 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.173%	577
Middle Eastern	0.0165%	6,062
Admixed American	0.0117%	8,575
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	8.47e-05%	1,180,011

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: CFHR5
Protein: p.Ser78Pro
Coding: c.232T>C
MANE Select: NM_030787
dbSNP: rs146025130
Type: single nucleotide variant
Location: chr1:196983058 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 78: a disulfide bond; the sushi 1 domain

Full CFHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR5 c.430+5G>T Uncertain significance ★★ same type
CFHR5 c.607+4A>G Uncertain significance ★★ same type
CFHR5 c.608-3T>A Uncertain significance ★★ same type
CFHR5 p.Arg132Gln Uncertain significance ★★ ⚠ same type
CFHR5 p.Arg132Trp Uncertain significance ★★ ⚠ same type
CFHR5 p.Arg354Gly Uncertain significance ★★ ⚠ same type
CFHR5 p.Arg356Cys Uncertain significance ★★ ⚠ same type
CFHR5 p.Arg364Ser Uncertain significance ★★ ⚠ 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/cfhr5-p-ser78pro (accessed [today's date]).

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