Is EFEMP2 p.Arg337Ter (c.1009C>T) pathogenic?

EFEMP2 p.Arg337Ter (c.1009C>T) is classified Pathogenic/Likely pathogenic in EFEMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-15). Very rare (popmax 0.00267%, afr); Associated with cutis laxa.

What condition is associated with EFEMP2 p.Arg337Ter (c.1009C>T)?

EFEMP2 p.Arg337Ter (c.1009C>T) is associated with cutis laxa (ClinVar).

How common is EFEMP2 p.Arg337Ter (c.1009C>T) in the general population?

EFEMP2 p.Arg337Ter (c.1009C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

EFEMP2 p.Arg337Ter

c.1009C>T · rs57685603 · VCV3075819

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

cutis laxa

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 11
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.97 · evaluated, not missing
Pangolin	Δ0.31	gain · loss 0.25 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP -2.3, phastCons 1
Overall
CADD	47.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,914 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,162 alleles · very rare

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.Arg337Ter
Coding: c.1009C>T
MANE Select: NM_016938
dbSNP: rs57685603
Type: single nucleotide variant
Location: chr11:65868022 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EFEMP2 p.Arg337Gln Uncertain significance ★★ ⚠ same residue
EFEMP2 p.Arg337= Likely benign ★★ same residue
EFEMP2 p.Arg337Gly Uncertain significance ★ same residue
EFEMP2 p.Arg279Cys Likely pathogenic ★★ same type
EFEMP2 p.Asp203Ala Pathogenic/Likely pathogenic ★★ same type
EFEMP2 p.Glu126Lys Pathogenic/Likely pathogenic ★★ same type
EFEMP2 p.Glu161Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
EFEMP2 p.Glu167Ter Pathogenic ★★ same type

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-arg337ter (accessed [today's date]).

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