Is EMP3 p.Val8Ile (c.22G>A) pathogenic?

EMP3 p.Val8Ile (c.22G>A) is classified Uncertain significance in EMP3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.1289); Ultra-rare (popmax 0.0208%, nfe).

How common is EMP3 p.Val8Ile (c.22G>A) in the general population?

EMP3 p.Val8Ile (c.22G>A) is ultra-rare (popmax 0.0208%, nfe) (gnomAD).

What do computational predictors say about EMP3 p.Val8Ile (c.22G>A)?

AlphaMissense predicts likely benign (score 0.1289) — an in-silico prediction, not a clinical call.

EMP3 p.Val8Ile

c.22G>A · rs773843651 · VCV2370600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1289 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0208%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1289	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,622 bp · p 0.1 · regional, not allelic
Overall
CADD	23.2	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 0.0208% European (non-Finnish) · 246/1,179,990 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0179%

Overall 0.0157% 253/1,613,858 alleles · ultra-rare exomes 246/1,461,834 · genomes 7/152,024 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0208%	4,797
African / African-American	0.00534%	18,720
Remaining individualsnot grpmax-eligible	0.0048%	20,826

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: EMP3
Protein: p.Val8Ile
Coding: c.22G>A
MANE Select: NM_001425
dbSNP: rs773843651
Type: single nucleotide variant
Location: chr19:48326866 (GRCh38)
Gene constraint: LOEUF 1.021 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.68

Full EMP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMP3 p.Ala119Val Uncertain significance ★ ⚠ same type
EMP3 p.Ala122Ser Uncertain significance ★ ⚠ same type
EMP3 p.Arg162Gln Uncertain significance ★ ⚠ same type
EMP3 p.Arg93Gln Uncertain significance ★ ⚠ same type
EMP3 p.Asn47Ser Uncertain significance ★ ⚠ same type
EMP3 p.Asp42Asn Uncertain significance ★ ⚠ same type
EMP3 p.Asp48Asn Uncertain significance ★ ⚠ same type
EMP3 p.Glu163Gln 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/emp3-p-val8ile (accessed [today's date]).

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