Is EMC4 p.Ala3Val (c.8C>T) pathogenic?

EMC4 p.Ala3Val (c.8C>T) is classified Uncertain significance in EMC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely benign (0.1011); Very rare (popmax 0.00279%, nfe).

How common is EMC4 p.Ala3Val (c.8C>T) in the general population?

EMC4 p.Ala3Val (c.8C>T) is very rare (popmax 0.00279%, nfe) (gnomAD).

What do computational predictors say about EMC4 p.Ala3Val (c.8C>T)?

AlphaMissense predicts likely benign (score 0.1011) — an in-silico prediction, not a clinical call.

EMC4 p.Ala3Val

c.8C>T · rs751425103 · VCV2527991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00279%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1011	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.70	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 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 4,670 bp · p 1.8e-05 · regional, not allelic
Overall
CADD	23.4	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 0.00279% European (non-Finnish) · 32/1,146,964 alleles

Filtering AF 0.00202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00173%

Overall 0.00213% 33/1,551,528 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00279%	35,843
Remaining individualsnot grpmax-eligible	0.00166%	60,092

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: EMC4
Protein: p.Ala3Val
Coding: c.8C>T
MANE Select: NM_016454
dbSNP: rs751425103
Type: single nucleotide variant
Location: chr15:34225122 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 67.65 · 9 PDB

Full EMC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC4 p.Arg108Ter Uncertain significance ★ same type
EMC4 p.Arg68His Uncertain significance ★ ⚠ same type
EMC4 p.Gly35Asp Uncertain significance ★ ⚠ same type
EMC4 p.Ile116Phe Uncertain significance ★ ⚠ same type
EMC4 p.Ile19Thr Uncertain significance ★ ⚠ same type
EMC4 p.Lys129Asn Uncertain significance ★ ⚠ same type
EMC4 p.Phe85Leu Uncertain significance ★ ⚠ same type
EMC4 p.Pro171His 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/emc4-p-ala3val (accessed [today's date]).

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