Is EFEMP2 p.Pro152His (c.455C>A) pathogenic?

EFEMP2 p.Pro152His (c.455C>A) is classified Uncertain significance in EFEMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-05). AlphaMissense: likely benign (0.3296); Ultra-rare (popmax 0.033%, mid); Associated with cutis laxa, autosomal recessive, type 1B.

What condition is associated with EFEMP2 p.Pro152His (c.455C>A)?

EFEMP2 p.Pro152His (c.455C>A) is associated with cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Pro152His (c.455C>A) in the general population?

EFEMP2 p.Pro152His (c.455C>A) is ultra-rare (popmax 0.033%, mid) (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.Pro152His (c.455C>A)?

AlphaMissense predicts likely benign (score 0.3296) — an in-silico prediction, not a clinical call.

EFEMP2 p.Pro152His

c.455C>A · rs143247661 · VCV2164472

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3296 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cutis laxa, autosomal recessive, type 1B

Computational evidence

Protein change
AlphaMissense	0.3296	likely benign
REVEL	0.697	pathogenic-leaning
SaProt	LLR -0.47	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	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	27.2	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00167% 27/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0064%	15,627
African / African-American	0.00133%	75,006
European (non-Finnish)	0.000678%	147,497

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.Pro152His
Coding: c.455C>A
MANE Select: NM_016938
dbSNP: rs143247661
Type: single nucleotide variant
Location: chr11:65870571 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 152: a disulfide bond; the egf-like 2; calcium-binding domain

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.Pro152Ala Uncertain significance ★ ⚠ same residue
EFEMP2 p.Pro152= Likely benign ★ 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

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-pro152his (accessed [today's date]).

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