Is EMC2 p.Leu208Val (c.622C>G) pathogenic?

EMC2 p.Leu208Val (c.622C>G) is classified Uncertain significance in EMC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-05). AlphaMissense: likely benign (0.1682); Ultra-rare (popmax 0.0157%, eas).

How common is EMC2 p.Leu208Val (c.622C>G) in the general population?

EMC2 p.Leu208Val (c.622C>G) is ultra-rare (popmax 0.0157%, eas) (gnomAD).

What do computational predictors say about EMC2 p.Leu208Val (c.622C>G)?

AlphaMissense predicts likely benign (score 0.1682) — an in-silico prediction, not a clinical call.

EMC2 p.Leu208Val

c.622C>G · rs189315527 · VCV2595076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1682 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1682	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 43 kb · p 0.67 · regional, not allelic
Overall
CADD	22.4	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 0.0157% East Asian · 7/44,644 alleles

Filtering AF 0.00729% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00517%

Overall 0.000499% 8/1,602,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0157%	6,378
Remaining individualsnot grpmax-eligible	0.00161%	62,080

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: EMC2
Protein: p.Leu208Val
Coding: c.622C>G
MANE Select: NM_014673
dbSNP: rs189315527
Type: single nucleotide variant
Location: chr8:108476812 (GRCh38)
Gene constraint: LOEUF 1.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.40 · 11 PDB
Residue 208: an α-helix

Full EMC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC2 p.Ala271Thr Uncertain significance ★ ⚠ same type
EMC2 p.Arg273Gln Uncertain significance ★ ⚠ same type
EMC2 p.Asn167Ser Uncertain significance ★ ⚠ same type
EMC2 p.Asp111Gly Uncertain significance ★ ⚠ same type
EMC2 p.Asp287His Uncertain significance ★ ⚠ same type
EMC2 p.Gln134Glu Uncertain significance ★ ⚠ same type
EMC2 p.Gln293His Uncertain significance ★ ⚠ same type
EMC2 p.Glu286Lys 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/emc2-p-leu208val (accessed [today's date]).

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