Is EMP3 p.Ile75Val (c.223A>G) pathogenic?

EMP3 p.Ile75Val (c.223A>G) is classified Uncertain significance in EMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0944); Very rare (popmax 0.00119%, nfe).

How common is EMP3 p.Ile75Val (c.223A>G) in the general population?

EMP3 p.Ile75Val (c.223A>G) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about EMP3 p.Ile75Val (c.223A>G)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

EMP3 p.Ile75Val

c.223A>G · VCV4664229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -5.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.28	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 3.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,622 bp · p 0.1 · regional, not allelic
Overall
CADD	14.86	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 0.00119% European (non-Finnish) · 14/1,179,980 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000958% 14/1,461,888 alleles · very rare

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.Ile75Val
Coding: c.223A>G
MANE Select: NM_001425
Type: single nucleotide variant
Location: chr19:48329393 (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-ile75val (accessed [today's date]).

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