Is ENAM p.Ser847Phe (c.2540C>T) pathogenic?

ENAM p.Ser847Phe (c.2540C>T) is classified Uncertain significance in ENAM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). AlphaMissense: likely benign (0.159); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ENAM p.Ser847Phe (c.2540C>T)?

ENAM p.Ser847Phe (c.2540C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ENAM p.Ser847Phe (c.2540C>T) in the general population?

ENAM p.Ser847Phe (c.2540C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ENAM p.Ser847Phe (c.2540C>T)?

AlphaMissense predicts likely benign (score 0.159) — an in-silico prediction, not a clinical call.

ENAM p.Ser847Phe

c.2540C>T · rs2545352633 · VCV2257760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.159	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -7.75	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 2.2	GERP 1.7, phastCons 0.98
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.57 · regional, not allelic
Overall
CADD	15.32	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 0.00133% African / African-American · 1/75,052 alleles

Overall 0.000137% 2/1,461,874 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,052
European (non-Finnish)	8.47e-05%	1,180,006

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.Ser847Phe
Coding: c.2540C>T
MANE Select: NM_031889
dbSNP: rs2545352633
Type: single nucleotide variant
Location: chr4:70643966 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 36.63

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-ser847phe (accessed [today's date]).

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