Is EFEMP2 p.Asn333= (c.999C>T) pathogenic?

EFEMP2 p.Asn333= (c.999C>T) is classified Likely benign in EFEMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-09). Very rare (popmax 0.00169%, nfe); Associated with cutis laxa, autosomal recessive, type 1B.

What condition is associated with EFEMP2 p.Asn333= (c.999C>T)?

EFEMP2 p.Asn333= (c.999C>T) is associated with cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Asn333= (c.999C>T) in the general population?

EFEMP2 p.Asn333= (c.999C>T) is very rare (popmax 0.00169%, nfe) (gnomAD).

How is Autosomal recessive cutis laxa type 1 inherited?

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

EFEMP2 p.Asn333=

c.999C>T · rs1463855646 · VCV3226943

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Conditions

cutis laxa, autosomal recessive, type 1B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.63	GERP -0.35, phastCons 1
Overall
CADD	9.238	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,179,986 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00136% 22/1,613,812 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	58,999
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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: EFEMP2
Protein: p.Asn333=
Coding: c.999C>T
MANE Select: NM_016938
dbSNP: rs1463855646
Type: single nucleotide variant
Location: chr11:65868032 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB

Full EFEMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cutis laxa, autosomal recessive, type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive cutis laxa type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

EFEMP2 p.Asn333Ser Uncertain significance ★ ⚠ same residue
EFEMP2 p.Arg279Cys Likely pathogenic ★★ same condition
EFEMP2 p.Asp203Ala Pathogenic/Likely pathogenic ★★ same condition
EFEMP2 p.Glu126Lys Pathogenic/Likely pathogenic ★★ same condition
EFEMP2 p.Glu161Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
EFEMP2 p.Glu167Ter Pathogenic ★★ same condition
EFEMP2 c.161-6C>G Uncertain significance ★★ same condition
EFEMP2 c.491-5C>G Uncertain significance ★★ 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/efemp2-p-asn333 (accessed [today's date]).

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