Is SEMA6B p.Arg99Pro (c.296G>C) pathogenic?

SEMA6B p.Arg99Pro (c.296G>C) is classified Uncertain significance in SEMA6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.2942); Ultra-rare (popmax 0.0134%, afr); Associated with Inborn genetic diseases.

What condition is associated with SEMA6B p.Arg99Pro (c.296G>C)?

SEMA6B p.Arg99Pro (c.296G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SEMA6B p.Arg99Pro (c.296G>C) in the general population?

SEMA6B p.Arg99Pro (c.296G>C) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about SEMA6B p.Arg99Pro (c.296G>C)?

AlphaMissense predicts likely benign (score 0.2942) — an in-silico prediction, not a clinical call.

SEMA6B p.Arg99Pro

c.296G>C · VCV4630473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2942	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.36, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 15 kb · p 0.11 · regional, not allelic
Overall
CADD	23.3	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 0.0134% African / African-American · 10/74,744 alleles

Filtering AF 0.00724% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00551%

Overall 0.000621% 10/1,609,542 alleles · ultra-rare

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.Arg99Pro
Coding: c.296G>C
MANE Select: NM_032108
Type: single nucleotide variant
Location: chr19:4557173 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 99: 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-arg99pro (accessed [today's date]).

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