Is SEMA6B p.Pro358= (c.1074C>T) pathogenic?

SEMA6B p.Pro358= (c.1074C>T) is classified Likely benign in SEMA6B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-21). Ultra-rare (popmax 0.0456%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SEMA6B p.Pro358= (c.1074C>T)?

SEMA6B p.Pro358= (c.1074C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SEMA6B p.Pro358= (c.1074C>T) in the general population?

SEMA6B p.Pro358= (c.1074C>T) is ultra-rare (popmax 0.0456%, nfe) (gnomAD).

SEMA6B p.Pro358=

c.1074C>T · rs10422855 · VCV3025124

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0456%, nfe)

Conditions

Inborn genetic diseases

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 -5.6	GERP -4.3
Overall
CADD	2.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0456% European (non-Finnish) · 538/1,180,006 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.04% 645/1,613,508 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.129%	774
European (non-Finnish)grpmax	0.0456%	2,193
Remaining individualsnot grpmax-eligible	0.0288%	3,472
South Asian	0.00549%	18,216
African / African-American	0.00267%	37,510

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SEMA6B
Protein: p.Pro358=
Coding: c.1074C>T
MANE Select: NM_032108
dbSNP: rs10422855
Type: single nucleotide variant
Location: chr19:4550846 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 358: the sema domain

Full SEMA6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEMA6B p.Gly538Ser Uncertain significance ★★ ⚠ same condition
SEMA6B p.Gly852Asp Uncertain significance ★★ ⚠ same condition
SEMA6B p.His180Asp Uncertain significance ★★ ⚠ same condition
SEMA6B p.Ser500Asn Uncertain significance ★★ ⚠ same condition
SEMA6B p.Ser851Cys Uncertain significance ★★ ⚠ same condition
SEMA6B p.Val88Leu Uncertain significance ★★ ⚠ same condition
SEMA6B p.Arg488Trp Likely benign ★★ same condition
SEMA6B p.Arg781Leu Benign/Likely benign ★★ 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/sema6b-p-pro358 (accessed [today's date]).

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