Is KBTBD13 p.Arg175Ser (c.523C>A) pathogenic?

KBTBD13 p.Arg175Ser (c.523C>A) is classified Uncertain significance in KBTBD13 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: likely pathogenic (0.8814); Very rare (popmax 9.02e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KBTBD13 p.Arg175Ser (c.523C>A)?

KBTBD13 p.Arg175Ser (c.523C>A) is associated with Inborn genetic diseases (ClinVar).

How common is KBTBD13 p.Arg175Ser (c.523C>A) in the general population?

KBTBD13 p.Arg175Ser (c.523C>A) is very rare (popmax 9.02e-05%, nfe) (gnomAD).

What do computational predictors say about KBTBD13 p.Arg175Ser (c.523C>A)?

AlphaMissense predicts likely pathogenic (score 0.8814) — an in-silico prediction, not a clinical call.

KBTBD13 p.Arg175Ser

c.523C>A · VCV4041319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.02e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8814	likely pathogenic · top 8% in KBTBD13
REVEL	0.352	indeterminate
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.32	unconstrained · MANE · 1,373 bp · p 5.3e-17 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.02e-05% European (non-Finnish) · 1/1,108,382 alleles

Overall 6.83e-05% 1/1,463,152 alleles · very rare exomes 1/1,310,956 · genomes 0/152,196 · joint denominator

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: KBTBD13
Protein: p.Arg175Ser
Coding: c.523C>A
MANE Select: NM_001101362
Type: single nucleotide variant
Location: chr15:65077338 (GRCh38)
Gene constraint: LOEUF 1.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.56

Full KBTBD13 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

KBTBD13 p.Arg175Cys Conflicting classifications of pathogenicity ★ same residue
KBTBD13 p.Arg175Pro Uncertain significance ★ ⚠ same residue
KBTBD13 p.Ala192Glu Uncertain significance ★★ ⚠ same condition
KBTBD13 p.Ala262Thr Uncertain significance ★★ ⚠ same condition
KBTBD13 p.Ala324Thr Uncertain significance ★★ ⚠ same condition
KBTBD13 p.Arg306Cys Uncertain significance ★★ ⚠ same condition
KBTBD13 p.Arg41Gln Uncertain significance ★★ ⚠ same condition
KBTBD13 p.Arg41Trp 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/kbtbd13-p-arg175ser (accessed [today's date]).

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