Is EMC1 p.Val708Ile (c.2122G>A) pathogenic?

EMC1 p.Val708Ile (c.2122G>A) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.0758); Rare (popmax 0.23%, mid); Associated with Inborn genetic diseases.

What condition is associated with EMC1 p.Val708Ile (c.2122G>A)?

EMC1 p.Val708Ile (c.2122G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EMC1 p.Val708Ile (c.2122G>A) in the general population?

EMC1 p.Val708Ile (c.2122G>A) is rare (popmax 0.23%, mid) (gnomAD).

What do computational predictors say about EMC1 p.Val708Ile (c.2122G>A)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

EMC1 p.Val708Ile

c.2122G>A · rs139714938 · VCV845914

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.23%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -7.82	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 4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 4e-06 · regional, not allelic
Overall
CADD	21.6	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 0.23% Middle Eastern · 14/6,084 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.00719% 116/1,614,106 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.23%	435
South Asian	0.0505%	1,980
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00398%	25,107
Finnishnot grpmax-eligible	0.00312%	32,016
Admixed American	0.00167%	60,014
African / African-American	0.00133%	74,930

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: EMC1
Protein: p.Val708Ile
Coding: c.2122G>A
MANE Select: NM_015047
dbSNP: rs139714938
Type: single nucleotide variant
Location: chr1:19227393 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 708: a β-strand

Full EMC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EMC1 p.Val708Phe Uncertain significance ★ ⚠ same residue
EMC1 p.Thr82Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
EMC1 c.1782+3G>A Uncertain significance ★★ same condition
EMC1 c.509+6G>A Uncertain significance ★★ same condition
EMC1 p.Ala152Val Uncertain significance ★★ ⚠ same condition
EMC1 p.Ala21Thr Uncertain significance ★★ ⚠ same condition
EMC1 p.Ala43Val Uncertain significance ★★ ⚠ same condition
EMC1 p.Ala509Val Uncertain significance ★★ ⚠ same condition

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/emc1-p-val708ile (accessed [today's date]).

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