Is CFHR5 p.Pro46Ser (c.136C>T) pathogenic?

CFHR5 p.Pro46Ser (c.136C>T) is classified Benign/Likely benign in CFHR5 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0869); Low-frequency (popmax 2.89%, mid); Associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II.

How common is CFHR5 p.Pro46Ser (c.136C>T) in the general population?

CFHR5 p.Pro46Ser (c.136C>T) is low-frequency (popmax 2.89%, mid) (gnomAD).

What do computational predictors say about CFHR5 p.Pro46Ser (c.136C>T)?

AlphaMissense predicts likely benign (score 0.0869) — an in-silico prediction, not a clinical call.

CFHR5 p.Pro46Ser

Q: What condition is associated with CFHR5 p.Pro46Ser (c.136C>T)?

CFHR5 p.Pro46Ser (c.136C>T) is associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II, atypical hemolytic-uremic syndrome (ClinVar).

c.136C>T · rs12097550 · VCV775635

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0869 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.89%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Computational evidence

Protein change
AlphaMissense	0.0869	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -8.37	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 -14	GERP -3.7
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	0.008	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 2.89% Middle Eastern · 175/6,060 alleles

Filtering AF 2.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.4%

Overall 0.622% 10,038/1,613,936 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.89%	35
African / African-American	2.07%	48
Ashkenazi Jewishnot grpmax-eligible	1.33%	75
Remaining individualsnot grpmax-eligible	0.786%	127
Admixed American	0.698%	143
European (non-Finnish)	0.552%	181
South Asian	0.494%	202
Amishnot grpmax-eligible	0.11%	912
Finnishnot grpmax-eligible	0.0672%	1,488
East Asian	0.00446%	22,426

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.Pro46Ser
Coding: c.136C>T
MANE Select: NM_030787
dbSNP: rs12097550
Type: single nucleotide variant
Location: chr1:196982962 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 46: a disulfide bond; the sushi 1 domain; a UniProt-annotated variant site (in)

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

Disease context

Also linked: atypical hemolytic-uremic syndrome

Similar variants

CFHR5 p.Arg85Gly Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asn216Ile Uncertain significance ★★ ⚠ same condition
CFHR5 p.Phe192Leu Uncertain significance ★★ ⚠ same condition
CFHR5 p.Pro26Ser Uncertain significance ★★ ⚠ same condition
CFHR5 p.Val430Ala Uncertain significance ★★ ⚠ same condition
CFHR5 c.254-8T>G Benign/Likely benign ★★ same condition
CFHR5 c.-20T>C Benign/Likely benign ★★ same condition
CFHR5 c.*741T>G Benign ★★ same condition

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-pro46ser (accessed [today's date]).

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