Is EMC1 p.Ile762Met (c.2286T>G) pathogenic?

EMC1 p.Ile762Met (c.2286T>G) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-30). AlphaMissense: likely benign (0.1025); Ultra-rare (popmax 0.0362%, sas).

How common is EMC1 p.Ile762Met (c.2286T>G) in the general population?

EMC1 p.Ile762Met (c.2286T>G) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

What do computational predictors say about EMC1 p.Ile762Met (c.2286T>G)?

AlphaMissense predicts likely benign (score 0.1025) — an in-silico prediction, not a clinical call.

EMC1 p.Ile762Met

c.2286T>G · rs376929368 · VCV1493605

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1025 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1025	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -9.89	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 -2.9	GERP -4.2
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 4e-06 · regional, not allelic
Overall
CADD	6.068	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 0.0362% South Asian · 33/91,076 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00359% 58/1,614,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0362%	2,760
African / African-American	0.0306%	3,263
Admixed American	0.00333%	30,011

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.Ile762Met
Coding: c.2286T>G
MANE Select: NM_015047
dbSNP: rs376929368
Type: single nucleotide variant
Location: chr1:19223486 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 762: a β-strand

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

Similar variants

EMC1 p.Ile762Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
EMC1 p.Ile762Thr Uncertain significance ★ ⚠ same residue
EMC1 p.Ile762Val Uncertain significance ★ ⚠ same residue
EMC1 c.287-1G>A Likely pathogenic ★★ same type
EMC1 c.787-1G>A Likely pathogenic ★★ same type
EMC1 p.Arg105Ter Pathogenic/Likely pathogenic ★★ same type
EMC1 p.Arg660Ter Pathogenic/Likely pathogenic ★★ same type
EMC1 p.Arg687Ter Pathogenic/Likely pathogenic ★★ 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/emc1-p-ile762met (accessed [today's date]).

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