Is CFH p.Arg127Pro (c.380G>C) pathogenic?

CFH p.Arg127Pro (c.380G>C) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9976); Very rare (popmax 6.21e-05%); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Arg127Pro (c.380G>C)?

CFH p.Arg127Pro (c.380G>C) is associated with age related macular degeneration 4 (ClinVar).

How common is CFH p.Arg127Pro (c.380G>C) in the general population?

CFH p.Arg127Pro (c.380G>C) is very rare (popmax 6.21e-05%) (gnomAD).

What do computational predictors say about CFH p.Arg127Pro (c.380G>C)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

CFH p.Arg127Pro

c.380G>C · VCV4291684

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.21e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

age related macular degeneration 4

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic · top 1% in CFH
REVEL	0.493	indeterminate
SaProt	LLR -14.08	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.21e-05%

Overall 6.21e-05% 1/1,610,408 alleles · very rare exomes 0/1,458,452 · genomes 1/151,956 · joint denominator

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.Arg127Pro
Coding: c.380G>C
MANE Select: NM_000186
Type: single nucleotide variant
Location: chr1:196676018 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 127: a β-strand; the sushi 2 domain; a UniProt-annotated variant site (in cfhd; with membranoproliferative glomerulonephritis)

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

Disease context

age related macular degeneration 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFH p.Arg127His Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH p.Arg127Leu Likely pathogenic ★ same residue
CFH p.Arg127Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same condition
CFH p.Cys431Ser Likely pathogenic ★★ 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-arg127pro (accessed [today's date]).

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