Is EFEMP2 p.Ala397Thr (c.1189G>A) pathogenic?

EFEMP2 p.Ala397Thr (c.1189G>A) is classified Pathogenic in EFEMP2 (ClinVar, Single submitter, 3 submitters; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.8294); Very rare (popmax 0.000254%, nfe); Associated with cutis laxa, autosomal recessive, type 1B.

What condition is associated with EFEMP2 p.Ala397Thr (c.1189G>A)?

EFEMP2 p.Ala397Thr (c.1189G>A) is associated with cutis laxa, autosomal recessive, type 1B, cutis laxa, autosomal recessive, type 1A (ClinVar).

How common is EFEMP2 p.Ala397Thr (c.1189G>A) in the general population?

EFEMP2 p.Ala397Thr (c.1189G>A) is very rare (popmax 0.000254%, 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.

What do computational predictors say about EFEMP2 p.Ala397Thr (c.1189G>A)?

AlphaMissense predicts likely pathogenic (score 0.8294) — an in-silico prediction, not a clinical call.

EFEMP2 p.Ala397Thr

c.1189G>A · rs193302868 · VCV39009

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8294 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cutis laxa, autosomal recessive, type 1B

Computational evidence

Protein change
AlphaMissense	0.8294	likely pathogenic ✓ concordant with ClinVar
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -12.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	33.0	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 0.000254% European (non-Finnish) · 3/1,180,040 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,830 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.Ala397Thr
Coding: c.1189G>A
MANE Select: NM_016938
dbSNP: rs193302868
Type: single nucleotide variant
Location: chr11:65867061 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 397: a UniProt-annotated variant site (in arcl1b; increased n-glycosylation; introduced an extra o-glycosylation site; does not affect secretion; decreased elastic fiber assembly; decreased interaction with collagen type iv trimer, fbn1, eln, ltbp1, loxl1 and loxl2; new fragments proteolyzed by elane)

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

Also linked: cutis laxa, autosomal recessive, type 1A

For Autosomal recessive cutis laxa type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

EFEMP2 p.Ala397Gly 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-ala397thr (accessed [today's date]).

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