Is SEMA3E p.Arg560= (c.1680A>G) pathogenic?

SEMA3E p.Arg560= (c.1680A>G) is classified Benign/Likely benign in SEMA3E (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-27). Rare (popmax 0.398%, eas); Associated with hypogonadotropic hypogonadism 7 with or without anosmia.

What condition is associated with SEMA3E p.Arg560= (c.1680A>G)?

SEMA3E p.Arg560= (c.1680A>G) is associated with hypogonadotropic hypogonadism 7 with or without anosmia, CHARGE syndrome (ClinVar).

How common is SEMA3E p.Arg560= (c.1680A>G) in the general population?

SEMA3E p.Arg560= (c.1680A>G) is rare (popmax 0.398%, eas) (gnomAD).

SEMA3E p.Arg560=

c.1680A>G · rs186628513 · VCV529142

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.398%, eas)

Conditions

hypogonadotropic hypogonadism 7 with or without anosmia

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 0.046	GERP -2.4, phastCons 0.96
Overall
CADD	8.336	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.398% East Asian · 178/44,770 alleles

Filtering AF 0.35% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.332%

Overall 0.0486% 784/1,613,252 alleles · rare exomes 690/1,461,004 · genomes 94/152,248 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.398%	252
Finnishnot grpmax-eligible	0.396%	253
Remaining individualsnot grpmax-eligible	0.0753%	1,328
Middle Eastern	0.0331%	3,025
European (non-Finnish)	0.0237%	4,228
South Asian	0.022%	4,552
African / African-American	0.004%	25,004
Admixed American	0.00334%	29,980

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.Arg560=
Coding: c.1680A>G
MANE Select: NM_012431
dbSNP: rs186628513
Type: single nucleotide variant
Location: chr7:83387038 (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

hypogonadotropic hypogonadism 7 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: CHARGE syndrome

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-arg560 (accessed [today's date]).

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