Is EMP2 p.Ser156Cys (c.466A>T) pathogenic?

EMP2 p.Ser156Cys (c.466A>T) is classified Uncertain significance in EMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely pathogenic (0.598); Ultra-rare (popmax 0.0238%, amr).

How common is EMP2 p.Ser156Cys (c.466A>T) in the general population?

EMP2 p.Ser156Cys (c.466A>T) is ultra-rare (popmax 0.0238%, amr) (gnomAD).

What do computational predictors say about EMP2 p.Ser156Cys (c.466A>T)?

AlphaMissense predicts likely pathogenic (score 0.598) — an in-silico prediction, not a clinical call.

EMP2 p.Ser156Cys

c.466A>T · rs776623915 · VCV2226461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.598 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0238%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.598	likely pathogenic
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -8.62	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 15 kb · p 0.029 · regional, not allelic
Overall
CADD	26.6	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 0.0238% Admixed American · 14/58,902 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00137% 22/1,603,528 alleles · ultra-rare exomes 15/1,451,474 · genomes 7/152,054 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0238%	4,207
Remaining individualsnot grpmax-eligible	0.00805%	12,417
African / African-American	0.00134%	74,658
European (non-Finnish)	0.00017%	587,182

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.Ser156Cys
Coding: c.466A>T
MANE Select: NM_001424
dbSNP: rs776623915
Type: single nucleotide variant
Location: chr16:10532943 (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.Ser156= Likely benign ★ same residue
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.Glu121Lys Uncertain significance ★★ ⚠ same type
EMP2 p.Ile69Met Uncertain significance ★★ ⚠ same type
EMP2 p.Thr43Ile 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/emp2-p-ser156cys (accessed [today's date]).

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