Is SEMA3E p.Ala2Val (c.5C>T) pathogenic?

SEMA3E p.Ala2Val (c.5C>T) is classified Uncertain significance in SEMA3E (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely benign (0.1539); Absent from gnomAD v4.1; Associated with CHARGE syndrome.

What condition is associated with SEMA3E p.Ala2Val (c.5C>T)?

SEMA3E p.Ala2Val (c.5C>T) is associated with CHARGE syndrome (ClinVar).

How common is SEMA3E p.Ala2Val (c.5C>T) in the general population?

SEMA3E p.Ala2Val (c.5C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SEMA3E p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.1539) — an in-silico prediction, not a clinical call.

SEMA3E p.Ala2Val

c.5C>T · rs763295904 · VCV2415043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1539 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHARGE syndrome

Computational evidence

Protein change
AlphaMissense	0.1539	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.75	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 4.3	GERP 0.46, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 281 kb · p 0.058 · regional, not allelic
Overall
CADD	21.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SEMA3E
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_012431
dbSNP: rs763295904
Type: single nucleotide variant
Location: chr7:83648538 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.62

Full SEMA3E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CHARGE syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEMA3E p.Ala2Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
SEMA3E p.Ala2= Likely benign ★ same residue
SEMA3E c.1500+5G>A Uncertain significance ★★ same condition
SEMA3E p.Ala112Val Uncertain significance ★★ ⚠ same condition
SEMA3E p.Ala290Val Uncertain significance ★★ ⚠ same condition
SEMA3E p.Ala383Ser Uncertain significance ★★ ⚠ same condition
SEMA3E p.Ala414Thr Uncertain significance ★★ ⚠ same condition
SEMA3E p.Ala437Thr 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/sema3e-p-ala2val (accessed [today's date]).

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