Is EMC1 p.Pro874His (c.2621C>A) pathogenic?

EMC1 p.Pro874His (c.2621C>A) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-15). AlphaMissense: likely pathogenic (0.8992); Very rare (popmax 0.0011%, sas).

How common is EMC1 p.Pro874His (c.2621C>A) in the general population?

EMC1 p.Pro874His (c.2621C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about EMC1 p.Pro874His (c.2621C>A)?

AlphaMissense predicts likely pathogenic (score 0.8992) — an in-silico prediction, not a clinical call.

EMC1 p.Pro874His

c.2621C>A · rs369308304 · VCV1307503

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8992	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -9.58	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.20	acceptor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 4e-06 · 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 0.0011% South Asian · 1/91,050 alleles

Overall 0.000137% 2/1,461,708 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,050
European (non-Finnish)	8.48e-05%	1,179,924

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.Pro874His
Coding: c.2621C>A
MANE Select: NM_015047
dbSNP: rs369308304
Type: single nucleotide variant
Location: chr1:19220815 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 874: a β-strand

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

Similar variants

EMC1 p.Pro874fs Pathogenic/Likely pathogenic ★★ 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
EMC1 p.Arg908Ter 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-pro874his (accessed [today's date]).

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