Is EFEMP1 p.Pro241Ser (c.721C>T) pathogenic?

EFEMP1 p.Pro241Ser (c.721C>T) is classified Uncertain significance in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-17). AlphaMissense: likely benign (0.1686); Rare (popmax 0.198%, mid).

How common is EFEMP1 p.Pro241Ser (c.721C>T) in the general population?

EFEMP1 p.Pro241Ser (c.721C>T) is rare (popmax 0.198%, mid) (gnomAD).

What do computational predictors say about EFEMP1 p.Pro241Ser (c.721C>T)?

AlphaMissense predicts likely benign (score 0.1686) — an in-silico prediction, not a clinical call.

EFEMP1 p.Pro241Ser

c.721C>T · rs756356313 · VCV1346366

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1686 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1686	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	18.92	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.198% Middle Eastern · 12/6,058 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0895%

Overall 0.000744% 12/1,613,208 alleles · rare exomes 12/1,461,000 · genomes 0/152,208 · joint denominator

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.Pro241Ser
Coding: c.721C>T
MANE Select: NM_001039348
dbSNP: rs756356313
Type: single nucleotide variant
Location: chr2:55877785 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 241: a UniProt-annotated variant site (in arcl1d; likely pathogenic); the egf-like 3; calcium-binding domain

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

Similar variants

EFEMP1 p.Arg345Trp Pathogenic/Likely pathogenic ★★ same type
EFEMP1 p.Ala104Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala126Pro Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala126Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala447Ser Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala447Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Arg148His Uncertain significance ★★ ⚠ same type
EFEMP1 p.Arg156Cys Uncertain significance ★★ ⚠ 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/efemp1-p-pro241ser (accessed [today's date]).

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