Is EFEMP1 p.Asp49Ala (c.146A>C) pathogenic?

EFEMP1 p.Asp49Ala (c.146A>C) is classified Conflicting classifications of pathogenicity in EFEMP1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-01). AlphaMissense: ambiguous (0.5284); Rare (popmax 0.16%, nfe); Associated with Doyne honeycomb retinal dystrophy.

What condition is associated with EFEMP1 p.Asp49Ala (c.146A>C)?

EFEMP1 p.Asp49Ala (c.146A>C) is associated with Doyne honeycomb retinal dystrophy (ClinVar).

How common is EFEMP1 p.Asp49Ala (c.146A>C) in the general population?

EFEMP1 p.Asp49Ala (c.146A>C) is rare (popmax 0.16%, nfe) (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.Asp49Ala (c.146A>C)?

AlphaMissense predicts ambiguous (score 0.5284) — an in-silico prediction, not a clinical call.

EFEMP1 p.Asp49Ala

c.146A>C · rs55849640 · VCV283832

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5284 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.16%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Doyne honeycomb retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.5284	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -4.08	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.51 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 0.94, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 4,438 bp · p 0.41 · regional, not allelic
Overall
CADD	22.6	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 0.16% European (non-Finnish) · 1,885/1,180,032 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.133% 2,141/1,614,236 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.16%	626
Remaining individualsnot grpmax-eligible	0.122%	823
Middle Eastern	0.115%	866
South Asian	0.101%	990
Finnishnot grpmax-eligible	0.0453%	2,208
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,278
African / African-American	0.0293%	3,412
Admixed American	0.0283%	3,531

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.Asp49Ala
Coding: c.146A>C
MANE Select: NM_001039348
dbSNP: rs55849640
Type: single nucleotide variant
Location: chr2:55918036 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 49: the egf-like 1; atypical domain

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.Arg345Trp Pathogenic/Likely pathogenic ★★ same condition
EFEMP1 p.Ala447Ser Uncertain significance ★★ ⚠ 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-asp49ala (accessed [today's date]).

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