Is SEMA6B p.Pro381= (c.1143C>T) pathogenic?

SEMA6B p.Pro381= (c.1143C>T) is classified Likely benign in SEMA6B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-01). Very rare (popmax 0.0022%, sas).

How common is SEMA6B p.Pro381= (c.1143C>T) in the general population?

SEMA6B p.Pro381= (c.1143C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

SEMA6B p.Pro381=

c.1143C>T · VCV3257112

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

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 -3.7
Overall
CADD	0.208	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,074 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000806% 13/1,613,164 alleles · very rare exomes 11/1,461,026 · genomes 2/152,138 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,230
South Asiangrpmax	0.0022%	45,537
Admixed American	0.00167%	59,984
African / African-American	0.00134%	74,906
European (non-Finnish)	0.000593%	168,542

Remaining individuals 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.Pro381=
Coding: c.1143C>T
MANE Select: NM_032108
Type: single nucleotide variant
Location: chr19:4550251 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 381: the sema domain

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

Similar variants

SEMA6B p.Pro381Ser Uncertain significance ★ ⚠ same residue
SEMA6B p.Gln660Ter Pathogenic/Likely pathogenic ★★ same type
SEMA6B p.Thr713Met Likely pathogenic ★★ ⚠ same type
SEMA6B p.Gly538Ser Uncertain significance ★★ ⚠ same type
SEMA6B p.Gly852Asp Uncertain significance ★★ ⚠ same type
SEMA6B p.His180Asp Uncertain significance ★★ ⚠ same type
SEMA6B p.Ser500Asn Uncertain significance ★★ ⚠ same type
SEMA6B p.Ser851Cys Uncertain significance ★★ ⚠ same type

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-pro381 (accessed [today's date]).

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