Is CFH p.Glu541Gly (c.1622A>G) pathogenic?

CFH p.Glu541Gly (c.1622A>G) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.2238); Ultra-rare (popmax 0.0165%, mid); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Glu541Gly (c.1622A>G)?

CFH p.Glu541Gly (c.1622A>G) is associated with age related macular degeneration 4 (ClinVar).

How common is CFH p.Glu541Gly (c.1622A>G) in the general population?

CFH p.Glu541Gly (c.1622A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CFH p.Glu541Gly (c.1622A>G)?

AlphaMissense predicts likely benign (score 0.2238) — an in-silico prediction, not a clinical call.

CFH p.Glu541Gly

c.1622A>G · rs2149103733 · VCV1383607

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2238 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

age related macular degeneration 4

Computational evidence

Protein change
AlphaMissense	0.2238	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -6.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,052 alleles

Overall 0.000657% 1/152,254 alleles · ultra-rare

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.Glu541Gly
Coding: c.1622A>G
MANE Select: NM_000186
dbSNP: rs2149103733
Type: single nucleotide variant
Location: chr1:196715695 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 541: the sushi 9 domain; a disulfide bond

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.Glu541Lys Uncertain significance ★★ ⚠ same residue
CFH p.Glu541Ala Uncertain significance ★ ⚠ 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
CFH p.Cys611Ter Pathogenic/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-glu541gly (accessed [today's date]).

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