Is CFH p.Arg53Leu (c.158G>T) pathogenic?

CFH p.Arg53Leu (c.158G>T) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-06). AlphaMissense: ambiguous (0.5035); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with CFH p.Arg53Leu (c.158G>T)?

CFH p.Arg53Leu (c.158G>T) is associated with Inborn genetic diseases, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Arg53Leu (c.158G>T) in the general population?

CFH p.Arg53Leu (c.158G>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CFH p.Arg53Leu (c.158G>T)?

AlphaMissense predicts ambiguous (score 0.5035) — an in-silico prediction, not a clinical call.

CFH p.Arg53Leu

c.158G>T · VCV3575090

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5035	ambiguous
REVEL	0.395	indeterminate
SaProt	LLR -9.25	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.86	GERP -0.59, phastCons 0.2
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	21.8	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 0.00267% African / African-American · 2/74,892 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,742 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,446
European (non-Finnish)	8.48e-05%	1,179,860

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.Arg53Leu
Coding: c.158G>T
MANE Select: NM_000186
Type: single nucleotide variant
Location: chr1:196673077 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 53: the sushi 1 domain; a disulfide bond

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

Also linked: basal laminar drusen hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency age related macular degeneration 4

Similar variants

CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same residue
CFH p.Arg53Gly Uncertain significance ★ ⚠ same residue
CFH p.Arg53His Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH p.Arg53Ser Likely pathogenic ★ same residue
CFH p.Arg53Pro Uncertain significance ★ ⚠ same residue
CFH p.Arg53= Likely benign ★ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.2236+1G>C 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-arg53leu (accessed [today's date]).

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