Is ENAM p.Pro894Ala (c.2680C>G) pathogenic?

ENAM p.Pro894Ala (c.2680C>G) is classified Uncertain significance in ENAM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely benign (0.0865); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with ENAM p.Pro894Ala (c.2680C>G)?

ENAM p.Pro894Ala (c.2680C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ENAM p.Pro894Ala (c.2680C>G) in the general population?

ENAM p.Pro894Ala (c.2680C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ENAM p.Pro894Ala (c.2680C>G)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

ENAM p.Pro894Ala

c.2680C>G · rs1026325425 · VCV3088824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.71, phastCons 0.001
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.57 · regional, not allelic
Overall
CADD	18.43	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00667% Admixed American · 4/60,000 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000372% 6/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,000
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	8.47e-05%	1,180,025

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: ENAM
Protein: p.Pro894Ala
Coding: c.2680C>G
MANE Select: NM_031889
dbSNP: rs1026325425
Type: single nucleotide variant
Location: chr4:70644106 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 36.63
Residue 894: the 'disordered' region

Full ENAM 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

Similar variants

ENAM p.Thr758Pro Uncertain significance ★★ ⚠ same condition
ENAM p.Ala72Thr Uncertain significance ★ ⚠ same condition
ENAM p.Ala752Ser Uncertain significance ★ ⚠ same condition
ENAM p.Ala790Thr Uncertain significance ★ ⚠ same condition
ENAM p.Ala796Thr Uncertain significance ★ ⚠ same condition
ENAM p.Ala798Gly Uncertain significance ★ ⚠ same condition
ENAM p.Ala888Ser Uncertain significance ★ ⚠ same condition
ENAM p.Arg105Trp Uncertain significance ★ ⚠ 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/enam-p-pro894ala (accessed [today's date]).

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