Is EFEMP1 p.Ala447Ser (c.1339G>T) pathogenic?

EFEMP1 p.Ala447Ser (c.1339G>T) is classified Uncertain significance in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-15). AlphaMissense: likely benign (0.2612); Ultra-rare (popmax 0.0661%, mid); Associated with Doyne honeycomb retinal dystrophy.

What condition is associated with EFEMP1 p.Ala447Ser (c.1339G>T)?

EFEMP1 p.Ala447Ser (c.1339G>T) is associated with Doyne honeycomb retinal dystrophy (ClinVar).

How common is EFEMP1 p.Ala447Ser (c.1339G>T) in the general population?

EFEMP1 p.Ala447Ser (c.1339G>T) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

How is Familial drusen inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EFEMP1 p.Ala447Ser (c.1339G>T)?

AlphaMissense predicts likely benign (score 0.2612) — an in-silico prediction, not a clinical call.

EFEMP1 p.Ala447Ser

c.1339G>T · rs746366927 · VCV2441181

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2612 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Doyne honeycomb retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.2612	likely benign
REVEL	0.718	pathogenic-leaning
SaProt	LLR -9.02	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	26.2	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 0.0661% Middle Eastern · 4/6,050 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00031% 5/1,613,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,513
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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: EFEMP1
Protein: p.Ala447Ser
Coding: c.1339G>T
MANE Select: NM_001039348
dbSNP: rs746366927
Type: single nucleotide variant
Location: chr2:55867216 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 447: a UniProt-annotated variant site (in arcl1d; likely pathogenic); the 'mediates interaction with timp3' region

Full EFEMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Doyne honeycomb retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial drusen (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

EFEMP1 p.Ala447Thr Uncertain significance ★★ ⚠ same residue
EFEMP1 p.Arg345Trp Pathogenic/Likely pathogenic ★★ same condition
EFEMP1 p.Glu374Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Met130Thr Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Pro373Leu Uncertain significance ★★ ⚠ same condition
EFEMP1 c.1001-14C>T Benign ★★ same condition
EFEMP1 c.518-11G>A Benign ★★ same condition
EFEMP1 c.518-13A>G Benign ★★ 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/efemp1-p-ala447ser (accessed [today's date]).

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