Is SEMA3E p.Ser3Phe (c.8C>T) pathogenic?

SEMA3E p.Ser3Phe (c.8C>T) is classified Uncertain significance in SEMA3E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-06). AlphaMissense: likely benign (0.0995); Very rare (popmax 8.48e-05%, nfe); Associated with CHARGE syndrome.

What condition is associated with SEMA3E p.Ser3Phe (c.8C>T)?

SEMA3E p.Ser3Phe (c.8C>T) is associated with CHARGE syndrome (ClinVar).

How common is SEMA3E p.Ser3Phe (c.8C>T) in the general population?

SEMA3E p.Ser3Phe (c.8C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SEMA3E p.Ser3Phe (c.8C>T)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

SEMA3E p.Ser3Phe

c.8C>T · VCV4805074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHARGE syndrome

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -8.01	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 5.6	GERP 1.4, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 281 kb · p 0.058 · regional, not allelic
Overall
CADD	19.22	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 8.48e-05% European (non-Finnish) · 1/1,179,390 alleles

Overall 6.2e-05% 1/1,613,014 alleles · very rare exomes 1/1,461,148 · genomes 0/151,866 · 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.Ser3Phe
Coding: c.8C>T
MANE Select: NM_012431
Type: single nucleotide variant
Location: chr7:83648535 (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.Ser3Tyr Uncertain significance ★ ⚠ same residue
SEMA3E p.Ser3= 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-ser3phe (accessed [today's date]).

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