Is CFH p.Pro381Leu (c.1142C>T) pathogenic?

CFH p.Pro381Leu (c.1142C>T) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.545); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with CFH p.Pro381Leu (c.1142C>T)?

CFH p.Pro381Leu (c.1142C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CFH p.Pro381Leu (c.1142C>T) in the general population?

CFH p.Pro381Leu (c.1142C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CFH p.Pro381Leu (c.1142C>T)?

AlphaMissense predicts ambiguous (score 0.545) — an in-silico prediction, not a clinical call.

CFH p.Pro381Leu

c.1142C>T · rs1170069737 · VCV2304323

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.545 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.545	ambiguous
REVEL	0.341	indeterminate
SaProt	LLR -10.42	damaging
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Constraint at this position
Conservation	phyloP 5.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 5.4e-05 · regional, not allelic
Overall
CADD	23.9	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 0.00134% African / African-American · 1/74,824 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,230 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,824
European (non-Finnish)	0.000509%	196,602

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: CFH
Protein: p.Pro381Leu
Coding: c.1142C>T
MANE Select: NM_000186
dbSNP: rs1170069737
Type: single nucleotide variant
Location: chr1:196689597 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 381: a β-strand; a disulfide bond; the sushi 6 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFH p.Pro381Thr Uncertain significance ★ ⚠ same residue
CFH p.Ala421Thr Uncertain significance ★★ ⚠ same condition
CFH p.Arg53Leu Uncertain significance ★★ ⚠ same condition
CFH p.Asn1050Ile Uncertain significance ★★ ⚠ same condition
CFH p.Asn660His Uncertain significance ★★ ⚠ same condition
CFH p.Asn75His Uncertain significance ★★ ⚠ same condition
CFH p.Asp276Glu Uncertain significance ★★ ⚠ same condition
CFH p.Asp855Asn Uncertain significance ★★ ⚠ 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/cfh-p-pro381leu (accessed [today's date]).

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