Is CFHR5 p.Phe192Leu (c.576T>G) pathogenic?

CFHR5 p.Phe192Leu (c.576T>G) is classified Uncertain significance in CFHR5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-09). AlphaMissense: likely pathogenic (0.9277); Ultra-rare (popmax 0.0203%, nfe); Associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II.

How common is CFHR5 p.Phe192Leu (c.576T>G) in the general population?

CFHR5 p.Phe192Leu (c.576T>G) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

What do computational predictors say about CFHR5 p.Phe192Leu (c.576T>G)?

AlphaMissense predicts likely pathogenic (score 0.9277) — an in-silico prediction, not a clinical call.

CFHR5 p.Phe192Leu

Q: What condition is associated with CFHR5 p.Phe192Leu (c.576T>G)?

CFHR5 p.Phe192Leu (c.576T>G) is associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (ClinVar).

c.576T>G · rs151134004 · VCV876520

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Computational evidence

Protein change
AlphaMissense	0.9277	likely pathogenic · top 5% in CFHR5
REVEL	0.278	benign-leaning
SaProt	LLR -8.34	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.16	GERP -0.76, phastCons 0.9
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	18.89	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 0.0203% European (non-Finnish) · 239/1,179,756 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0165% 266/1,613,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0406%	2,466
European (non-Finnish)grpmax	0.0203%	4,936
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Admixed American	0.00833%	12,001
African / African-American	0.00533%	18,757

Ashkenazi Jewish 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: CFHR5
Protein: p.Phe192Leu
Coding: c.576T>G
MANE Select: NM_030787
dbSNP: rs151134004
Type: single nucleotide variant
Location: chr1:196994225 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 192: a disulfide bond; the sushi 3 domain

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

Disease context

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR5 p.Arg85Gly 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
CFHR5 c.*802T>G Benign ★★ same condition
CFHR5 p.Asp169= Benign/Likely 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-phe192leu (accessed [today's date]).

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