Is SEMA3E p.Ala2= (c.6A>G) pathogenic?

SEMA3E p.Ala2= (c.6A>G) is classified Likely benign in SEMA3E (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-31). Very rare (popmax 0.00446%, eas); Associated with CHARGE syndrome.

What condition is associated with SEMA3E p.Ala2= (c.6A>G)?

SEMA3E p.Ala2= (c.6A>G) is associated with CHARGE syndrome (ClinVar).

How common is SEMA3E p.Ala2= (c.6A>G) in the general population?

SEMA3E p.Ala2= (c.6A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

SEMA3E p.Ala2=

c.6A>G · VCV3608110

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

CHARGE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5	GERP 0.95, phastCons 0.68
Overall
CADD	11.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,808 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,612,846 alleles · very rare exomes 2/1,460,830 · genomes 0/152,016 · joint denominator

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: SEMA3E
Protein: p.Ala2=
Coding: c.6A>G
MANE Select: NM_012431
Type: single nucleotide variant
Location: chr7:83648537 (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.Ala2Val Uncertain significance ★ ⚠ 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-ala2 (accessed [today's date]).

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