Is SEMA3E p.Ala201= (c.603G>T) pathogenic?

SEMA3E p.Ala201= (c.603G>T) is classified Benign in SEMA3E (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 83.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with CHARGE syndrome.

What condition is associated with SEMA3E p.Ala201= (c.603G>T)?

SEMA3E p.Ala201= (c.603G>T) is associated with CHARGE syndrome (ClinVar).

SEMA3E p.Ala201=

Q: How common is SEMA3E p.Ala201= (c.603G>T) in the general population?

SEMA3E p.Ala201= (c.603G>T) is common (popmax 83.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.603G>T · rs2722985 · VCV260255

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 83.5%, eas) — too common for a highly-penetrant pathogenic allele

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 -8.2	GERP -5.3
Overall
CADD	0.702	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 83.5% East Asian · 37,426/44,844 alleles

Filtering AF 82.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 82.5%

Overall 59.5% 959,215/1,613,168 alleles · common exomes 882,062/1,461,086 · genomes 77,153/152,082 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	83.5%	1
Amishnot grpmax-eligible	68.4%	1
Admixed American	68.2%	1
Finnishnot grpmax-eligible	66.9%	1
South Asian	65.4%	2
European (non-Finnish)	60.3%	2
Remaining individualsnot grpmax-eligible	58%	2
Middle Eastern	48.4%	2
Ashkenazi Jewishnot grpmax-eligible	44.1%	2
African / African-American	20%	5

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.Ala201=
Coding: c.603G>T
MANE Select: NM_012431
dbSNP: rs2722985
Type: single nucleotide variant
Location: chr7:83408435 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.62
Residue 201: 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.Ala201Glu 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-ala201 (accessed [today's date]).

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