Is EMC1 p.Ala233Val (c.698C>T) pathogenic?

EMC1 p.Ala233Val (c.698C>T) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-20). AlphaMissense: likely benign (0.2039); Very rare (popmax 0.000508%, nfe); Associated with cerebellar atrophy, visual impairment, and psychomotor retardation;.

What condition is associated with EMC1 p.Ala233Val (c.698C>T)?

EMC1 p.Ala233Val (c.698C>T) is associated with cerebellar atrophy, visual impairment, and psychomotor retardation; (ClinVar).

How common is EMC1 p.Ala233Val (c.698C>T) in the general population?

EMC1 p.Ala233Val (c.698C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about EMC1 p.Ala233Val (c.698C>T)?

AlphaMissense predicts likely benign (score 0.2039) — an in-silico prediction, not a clinical call.

EMC1 p.Ala233Val

c.698C>T · rs2536784855 · VCV1805929

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2039 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebellar atrophy, visual impairment, and psychomotor retardation;

Computational evidence

Protein change
AlphaMissense	0.2039	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -8.82	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.24 · regional, not allelic
Overall
CADD	26.5	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 0.000508% European (non-Finnish) · 6/1,180,018 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,876 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: EMC1
Protein: p.Ala233Val
Coding: c.698C>T
MANE Select: NM_015047
dbSNP: rs2536784855
Type: single nucleotide variant
Location: chr1:19240385 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 233: a turn; a disulfide bond

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

Disease context

cerebellar atrophy, visual impairment, and psychomotor retardation; — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EMC1 p.Ala233= Likely benign ★ same residue
EMC1 c.287-1G>A Likely pathogenic ★★ same condition
EMC1 c.787-1G>A Likely pathogenic ★★ same condition
EMC1 p.Arg660Ter Pathogenic/Likely pathogenic ★★ same condition
EMC1 p.Arg69Ter Pathogenic/Likely pathogenic ★★ same condition
EMC1 p.Leu266Ter Pathogenic/Likely pathogenic ★★ same condition
EMC1 p.Met1Arg Pathogenic/Likely pathogenic ★★ same condition
EMC1 p.Thr82Met Pathogenic/Likely pathogenic ★★ ⚠ 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-ala233val (accessed [today's date]).

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