Is EMP2 p.Glu121Lys (c.361G>A) pathogenic?

EMP2 p.Glu121Lys (c.361G>A) is classified Uncertain significance in EMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-04). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0444%, nfe).

How common is EMP2 p.Glu121Lys (c.361G>A) in the general population?

EMP2 p.Glu121Lys (c.361G>A) is ultra-rare (popmax 0.0444%, nfe) (gnomAD).

What do computational predictors say about EMP2 p.Glu121Lys (c.361G>A)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

EMP2 p.Glu121Lys

c.361G>A · rs143318656 · VCV2077729

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0444%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -3.7
Regional constraint	o/e 1.15	unconstrained · MANE · 15 kb · p 0.029 · regional, not allelic
Overall
CADD	1.061	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 0.0444% European (non-Finnish) · 523/1,177,960 alleles

Filtering AF 0.0412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0399%

Overall 0.0344% 553/1,609,706 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0444%	2,252
Finnishnot grpmax-eligible	0.0172%	5,805
Remaining individualsnot grpmax-eligible	0.016%	6,234
African / African-American	0.012%	8,314

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: EMP2
Protein: p.Glu121Lys
Coding: c.361G>A
MANE Select: NM_001424
dbSNP: rs143318656
Type: single nucleotide variant
Location: chr16:10533048 (GRCh38)
Gene constraint: LOEUF 1.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89

Full EMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMP2 p.Ala63Val Uncertain significance ★★ ⚠ same type
EMP2 p.Ala78Thr Uncertain significance ★★ ⚠ same type
EMP2 p.Arg120His Uncertain significance ★★ ⚠ same type
EMP2 p.Arg166His Uncertain significance ★★ ⚠ same type
EMP2 p.Ile69Met Uncertain significance ★★ ⚠ same type
EMP2 p.Thr43Ile Uncertain significance ★★ ⚠ same type
EMP2 p.Tyr143His Uncertain significance ★★ ⚠ same type
EMP2 c.169+9G>C Benign/Likely benign ★★ 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/emp2-p-glu121lys (accessed [today's date]).

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