Is ENAH p.Ser295Phe (c.884C>T) pathogenic?

ENAH p.Ser295Phe (c.884C>T) is classified Uncertain significance in ENAH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely benign (0.2024); Ultra-rare (popmax 0.0122%, eas).

How common is ENAH p.Ser295Phe (c.884C>T) in the general population?

ENAH p.Ser295Phe (c.884C>T) is ultra-rare (popmax 0.0122%, eas) (gnomAD).

What do computational predictors say about ENAH p.Ser295Phe (c.884C>T)?

AlphaMissense predicts likely benign (score 0.2024) — an in-silico prediction, not a clinical call.

ENAH p.Ser295Phe

c.884C>T · rs1406664545 · VCV3088815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2024 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2024	likely benign
REVEL	0.439	indeterminate
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 18 kb · p 0.13 · regional, not allelic
Overall
CADD	23.1	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 0.0122% East Asian · 5/40,956 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.000388% 6/1,547,346 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0122%	8,191
Remaining individualsnot grpmax-eligible	0.00167%	59,870

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: ENAH
Protein: p.Ser295Phe
Coding: c.884C>T
MANE Select: NM_018212
dbSNP: rs1406664545
Type: single nucleotide variant
Location: chr1:225517225 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.69 · 28 PDB
Residue 295: the 'disordered' region

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

Similar variants

ENAH p.Ser265Leu Likely benign ★★ same type
ENAH c.1538+2899C>T Uncertain significance ★ ⚠ same type
ENAH p.Ala393Val Uncertain significance ★ ⚠ same type
ENAH p.Arg152Trp Uncertain significance ★ ⚠ same type
ENAH p.Arg158Trp Uncertain significance ★ ⚠ same type
ENAH p.Arg165Lys Uncertain significance ★ ⚠ same type
ENAH p.Arg173Thr Uncertain significance ★ ⚠ same type
ENAH p.Arg185Leu Uncertain significance ★ ⚠ 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/enah-p-ser295phe (accessed [today's date]).

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