Is EFEMP1 p.Leu451= (c.1353C>T) pathogenic?

EFEMP1 p.Leu451= (c.1353C>T) is classified Uncertain significance in EFEMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00223%, eas); Associated with Doyne honeycomb retinal dystrophy.

What condition is associated with EFEMP1 p.Leu451= (c.1353C>T)?

EFEMP1 p.Leu451= (c.1353C>T) is associated with Doyne honeycomb retinal dystrophy (ClinVar).

How common is EFEMP1 p.Leu451= (c.1353C>T) in the general population?

EFEMP1 p.Leu451= (c.1353C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Familial drusen inherited?

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

EFEMP1 p.Leu451=

c.1353C>T · rs1399879099 · VCV899334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Doyne honeycomb retinal dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.33	GERP -4.9, phastCons 0.048
Overall
CADD	3.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,864 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00103% 15/1,461,668 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,864
South Asian	0.0022%	45,529
Remaining individualsnot grpmax-eligible	0.0016%	62,498
European (non-Finnish)	0.000932%	107,265

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.Leu451=
Coding: c.1353C>T
MANE Select: NM_001039348
dbSNP: rs1399879099
Type: single nucleotide variant
Location: chr2:55867202 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 451: 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.Leu451Phe Uncertain significance ★★ ⚠ same residue
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

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-leu451 (accessed [today's date]).

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