Is SEMA3E p.Pro535Ser (c.1603C>T) pathogenic?

SEMA3E p.Pro535Ser (c.1603C>T) is classified Uncertain significance in SEMA3E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-31). AlphaMissense: likely pathogenic (0.9914); Absent from gnomAD v4.1; Associated with CHARGE syndrome.

What condition is associated with SEMA3E p.Pro535Ser (c.1603C>T)?

SEMA3E p.Pro535Ser (c.1603C>T) is associated with CHARGE syndrome (ClinVar).

How common is SEMA3E p.Pro535Ser (c.1603C>T) in the general population?

SEMA3E p.Pro535Ser (c.1603C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SEMA3E p.Pro535Ser (c.1603C>T)?

AlphaMissense predicts likely pathogenic (score 0.9914) — an in-silico prediction, not a clinical call.

SEMA3E p.Pro535Ser

c.1603C>T · VCV4803742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9914 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHARGE syndrome

Computational evidence

Protein change
AlphaMissense	0.9914	likely pathogenic · top 4% in SEMA3E
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -13.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 281 kb · p 0.058 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Pro535Ser
Coding: c.1603C>T
MANE Select: NM_012431
Type: single nucleotide variant
Location: chr7:83392619 (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 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
SEMA3E p.Ala609Val 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-pro535ser (accessed [today's date]).

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