Is BTBD1 p.Cys400Ser (c.1198T>A) pathogenic?

BTBD1 p.Cys400Ser (c.1198T>A) is classified Uncertain significance in BTBD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.6262); Very rare (popmax 0.00585%, nfe).

How common is BTBD1 p.Cys400Ser (c.1198T>A) in the general population?

BTBD1 p.Cys400Ser (c.1198T>A) is very rare (popmax 0.00585%, nfe) (gnomAD).

What do computational predictors say about BTBD1 p.Cys400Ser (c.1198T>A)?

AlphaMissense predicts likely pathogenic (score 0.6262) — an in-silico prediction, not a clinical call.

BTBD1 p.Cys400Ser

c.1198T>A · VCV4646885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6262	likely pathogenic
REVEL	0.734	pathogenic-leaning
SaProt	LLR -8.34	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 32 kb · p 0.0075 · regional, not allelic
Overall
CADD	24.2	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 0.00585% European (non-Finnish) · 69/1,179,978 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.0044% 71/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00585%	17,101
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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: BTBD1
Protein: p.Cys400Ser
Coding: c.1198T>A
MANE Select: NM_025238
Type: single nucleotide variant
Location: chr15:83018799 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.99

Full BTBD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD1 p.Ala162Gly Uncertain significance ★ ⚠ same type
BTBD1 p.Ala162Val Uncertain significance ★ ⚠ same type
BTBD1 p.Ala16Gly Uncertain significance ★ ⚠ same type
BTBD1 p.Ala23Pro Uncertain significance ★ ⚠ same type
BTBD1 p.Ala82Val Uncertain significance ★ ⚠ same type
BTBD1 p.Ala84Val Uncertain significance ★ ⚠ same type
BTBD1 p.Ala8Thr Uncertain significance ★ ⚠ same type
BTBD1 p.Arg236Gln 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/btbd1-p-cys400ser (accessed [today's date]).

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