Is CFH p.Thr46Ala (c.136A>G) pathogenic?

CFH p.Thr46Ala (c.136A>G) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.1572); Very rare (popmax 0.0028%, nfe); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Thr46Ala (c.136A>G)?

CFH p.Thr46Ala (c.136A>G) is associated with age related macular degeneration 4 (ClinVar).

How common is CFH p.Thr46Ala (c.136A>G) in the general population?

CFH p.Thr46Ala (c.136A>G) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about CFH p.Thr46Ala (c.136A>G)?

AlphaMissense predicts likely benign (score 0.1572) — an in-silico prediction, not a clinical call.

CFH p.Thr46Ala

c.136A>G · rs778461886 · VCV1469866

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

age related macular degeneration 4

Computational evidence

Protein change
AlphaMissense	0.1572	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -9.23	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 4.6	GERP -0.58, phastCons 0.17
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	20.6	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 0.0028% European (non-Finnish) · 33/1,179,968 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00223% 36/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,825
European (non-Finnish)grpmax	0.0028%	35,757

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr46Ala
Coding: c.136A>G
MANE Select: NM_000186
dbSNP: rs778461886
Type: single nucleotide variant
Location: chr1:196673055 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 46: the sushi 1 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.Thr46= Likely benign ★ 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
CFH p.Gln859Ter 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-thr46ala (accessed [today's date]).

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