Is EMC1 p.Gln246Pro (c.737A>C) pathogenic?

EMC1 p.Gln246Pro (c.737A>C) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-27). AlphaMissense: ambiguous (0.4263); Very rare (popmax 0.00178%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EMC1 p.Gln246Pro (c.737A>C)?

EMC1 p.Gln246Pro (c.737A>C) is associated with Inborn genetic diseases, cerebellar atrophy, visual impairment, and psychomotor retardation; (ClinVar).

How common is EMC1 p.Gln246Pro (c.737A>C) in the general population?

EMC1 p.Gln246Pro (c.737A>C) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about EMC1 p.Gln246Pro (c.737A>C)?

AlphaMissense predicts ambiguous (score 0.4263) — an in-silico prediction, not a clinical call.

EMC1 p.Gln246Pro

c.737A>C · rs200901424 · VCV1312336

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4263	ambiguous
REVEL	0.053	moderately benign-leaning
SaProt	LLR -10.37	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.24 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,036 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0013% 21/1,614,080 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.Gln246Pro
Coding: c.737A>C
MANE Select: NM_015047
dbSNP: rs200901424
Type: single nucleotide variant
Location: chr1:19240346 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 246: 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

Also linked: cerebellar atrophy, visual impairment, and psychomotor retardation;

Similar variants

EMC1 p.Gln246Arg Uncertain significance ★★ ⚠ same residue
EMC1 p.Gln246His Uncertain significance ★ ⚠ 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

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-gln246pro (accessed [today's date]).

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