Is EFEMP1 p.Pro72Leu (c.215C>T) pathogenic?

EFEMP1 p.Pro72Leu (c.215C>T) is classified Uncertain significance in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.9726); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with EFEMP1 p.Pro72Leu (c.215C>T)?

EFEMP1 p.Pro72Leu (c.215C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EFEMP1 p.Pro72Leu (c.215C>T) in the general population?

EFEMP1 p.Pro72Leu (c.215C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EFEMP1 p.Pro72Leu (c.215C>T)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

EFEMP1 p.Pro72Leu

c.215C>T · rs753826959 · VCV3087515

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.17	constrained · MANE · 57 bp · p 5.5e-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 0.00167% Admixed American · 1/59,990 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,990
European (non-Finnish)	0.000169%	590,023

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.Pro72Leu
Coding: c.215C>T
MANE Select: NM_001039348
dbSNP: rs753826959
Type: single nucleotide variant
Location: chr2:55917967 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67

Full EFEMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EFEMP1 p.Pro72= Likely benign ★★ same residue
EFEMP1 p.Ala126Pro Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Ala126Thr Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Ala447Thr Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Arg208Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Arg362Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Arg401Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Asn80Ser 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/efemp1-p-pro72leu (accessed [today's date]).

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