Is SEMA3E p.Asp449= (c.1347C>T) pathogenic?

SEMA3E p.Asp449= (c.1347C>T) is classified Likely benign in SEMA3E (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0317%, amr); Associated with CHARGE syndrome.

What condition is associated with SEMA3E p.Asp449= (c.1347C>T)?

SEMA3E p.Asp449= (c.1347C>T) is associated with CHARGE syndrome (ClinVar).

How common is SEMA3E p.Asp449= (c.1347C>T) in the general population?

SEMA3E p.Asp449= (c.1347C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

SEMA3E p.Asp449=

c.1347C>T · rs148072082 · VCV699807

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

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 0.67	GERP -5.4, phastCons 0.91
Overall
CADD	7.008	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/60,008 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00335% 54/1,612,390 alleles · ultra-rare exomes 39/1,460,146 · genomes 15/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
Remaining individualsnot grpmax-eligible	0.00961%	10,410
East Asian	0.00669%	14,950
African / African-American	0.00533%	18,747
European (non-Finnish)	0.00187%	53,566

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.Asp449=
Coding: c.1347C>T
MANE Select: NM_012431
dbSNP: rs148072082
Type: single nucleotide variant
Location: chr7:83400047 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.62
Residue 449: the sema domain

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.Asp449Val 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
SEMA3E p.Ala508Thr 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-asp449 (accessed [today's date]).

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