Is EMC1 p.Arg445Cys (c.1333C>T) pathogenic?

EMC1 p.Arg445Cys (c.1333C>T) is classified Conflicting classifications of pathogenicity in EMC1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-20). AlphaMissense: likely pathogenic (0.9286); Ultra-rare (popmax 0.0539%, sas).

How common is EMC1 p.Arg445Cys (c.1333C>T) in the general population?

EMC1 p.Arg445Cys (c.1333C>T) is ultra-rare (popmax 0.0539%, sas) (gnomAD).

What do computational predictors say about EMC1 p.Arg445Cys (c.1333C>T)?

AlphaMissense predicts likely pathogenic (score 0.9286) — an in-silico prediction, not a clinical call.

EMC1 p.Arg445Cys

c.1333C>T · rs578239910 · VCV1520091

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9286 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0539%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9286	likely pathogenic
REVEL	0.637	indeterminate
SaProt	LLR -15.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.24 · regional, not allelic
Overall
CADD	32.0	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 0.0539% South Asian · 49/90,874 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0375%

Overall 0.00465% 75/1,613,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0539%	1,855
Remaining individualsnot grpmax-eligible	0.0048%	20,813
East Asian	0.00223%	44,764
European (non-Finnish)	0.00178%	56,166
African / African-American	0.00133%	75,022

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.Arg445Cys
Coding: c.1333C>T
MANE Select: NM_015047
dbSNP: rs578239910
Type: single nucleotide variant
Location: chr1:19235229 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 445: a β-strand

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

Similar variants

EMC1 p.Arg445= Likely benign ★★ same residue
EMC1 p.Arg445His 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
EMC1 p.Arg69Ter 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-arg445cys (accessed [today's date]).

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