Is EMC1 p.Pro897Leu (c.2690C>T) pathogenic?

EMC1 p.Pro897Leu (c.2690C>T) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely pathogenic (0.5986); Very rare (popmax 0.00801%, afr).

How common is EMC1 p.Pro897Leu (c.2690C>T) in the general population?

EMC1 p.Pro897Leu (c.2690C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about EMC1 p.Pro897Leu (c.2690C>T)?

AlphaMissense predicts likely pathogenic (score 0.5986) — an in-silico prediction, not a clinical call.

EMC1 p.Pro897Leu

c.2690C>T · rs146583625 · VCV1428569

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5986	likely pathogenic
REVEL	0.594	indeterminate
SaProt	LLR -12.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 4e-06 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00801% African / African-American · 6/74,878 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00353% 57/1,613,868 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,480
Remaining individualsnot grpmax-eligible	0.008%	12,498
South Asian	0.00439%	22,768
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00333%	29,986
European (non-Finnish)	0.00322%	31,053
Finnishnot grpmax-eligible	0.00156%	63,998

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.Pro897Leu
Coding: c.2690C>T
MANE Select: NM_015047
dbSNP: rs146583625
Type: single nucleotide variant
Location: chr1:19219681 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 897: an α-helix

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

Similar variants

EMC1 p.Pro897= Likely benign ★ 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-pro897leu (accessed [today's date]).

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