Is EMC1 p.Leu295Ser (c.884T>C) pathogenic?

EMC1 p.Leu295Ser (c.884T>C) is classified Benign/Likely benign in EMC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely pathogenic (0.7199); Common (popmax 6.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with EMC1 p.Leu295Ser (c.884T>C)?

EMC1 p.Leu295Ser (c.884T>C) is associated with inherited retinal dystrophy, cerebellar atrophy, visual impairment, and psychomotor retardation; (ClinVar).

What do computational predictors say about EMC1 p.Leu295Ser (c.884T>C)?

AlphaMissense predicts likely pathogenic (score 0.7199) — an in-silico prediction, not a clinical call.

EMC1 p.Leu295Ser

Q: How common is EMC1 p.Leu295Ser (c.884T>C) in the general population?

EMC1 p.Leu295Ser (c.884T>C) is common (popmax 6.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.884T>C · rs3850531 · VCV1170013

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7199 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.8%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.7199	likely pathogenic
REVEL	0.212	benign-leaning
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.24 · regional, not allelic
Overall
CADD	25.3	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 6.8% East Asian · 3,049/44,866 alleles

Filtering AF 6.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.51%

Overall 0.474% 7,650/1,614,152 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	6.8%	15
South Asian	2.7%	37
Admixed American	2.42%	41
Remaining individualsnot grpmax-eligible	0.59%	169
Finnishnot grpmax-eligible	0.172%	582
Middle Eastern	0.132%	758
African / African-American	0.024%	4,170
European (non-Finnish)	0.0156%	6,413

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.Leu295Ser
Coding: c.884T>C
MANE Select: NM_015047
dbSNP: rs3850531
Type: single nucleotide variant
Location: chr1:19239888 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 295: a UniProt-annotated variant site (in)

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

EMC1 p.Leu295Phe 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
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-leu295ser (accessed [today's date]).

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