Is CFH p.Ser58Ala (c.172T>G) pathogenic?

CFH p.Ser58Ala (c.172T>G) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.1827); Ultra-rare (popmax 0.0966%, amr); Associated with basal laminar drusen.

What condition is associated with CFH p.Ser58Ala (c.172T>G)?

CFH p.Ser58Ala (c.172T>G) is associated with basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1, complement factor H deficiency (ClinVar).

How common is CFH p.Ser58Ala (c.172T>G) in the general population?

CFH p.Ser58Ala (c.172T>G) is ultra-rare (popmax 0.0966%, amr) (gnomAD).

What do computational predictors say about CFH p.Ser58Ala (c.172T>G)?

AlphaMissense predicts likely benign (score 0.1827) — an in-silico prediction, not a clinical call.

CFH p.Ser58Ala

c.172T>G · rs141336681 · VCV874052

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0966%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

basal laminar drusen

Computational evidence

Protein change
AlphaMissense	0.1827	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP -0.56, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	18.68	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 0.0966% Admixed American · 58/60,014 alleles

Filtering AF 0.0767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0696%

Overall 0.0372% 601/1,614,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0966%	1,035
European (non-Finnish)	0.0434%	2,305
Remaining individualsnot grpmax-eligible	0.024%	4,167
Finnishnot grpmax-eligible	0.0172%	5,821
African / African-American	0.00667%	15,001

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.Ser58Ala
Coding: c.172T>G
MANE Select: NM_000186
dbSNP: rs141336681
Type: single nucleotide variant
Location: chr1:196673091 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 58: the sushi 1 domain; a disulfide bond

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

Disease context

basal laminar drusen — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.350+1G>T Pathogenic/Likely pathogenic ★★ same condition
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg1215Leu Likely pathogenic ★★ same condition
CFH p.Arg1215Ter 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-ser58ala (accessed [today's date]).

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