Is BTBD1 p.Arg320Gln (c.959G>A) pathogenic?

BTBD1 p.Arg320Gln (c.959G>A) is classified Uncertain significance in BTBD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-30). AlphaMissense: likely benign (0.1717); Ultra-rare (popmax 0.0201%, eas).

How common is BTBD1 p.Arg320Gln (c.959G>A) in the general population?

BTBD1 p.Arg320Gln (c.959G>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about BTBD1 p.Arg320Gln (c.959G>A)?

AlphaMissense predicts likely benign (score 0.1717) — an in-silico prediction, not a clinical call.

BTBD1 p.Arg320Gln

c.959G>A · rs375845805 · VCV2592879

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1717	likely benign
REVEL	0.46	indeterminate
SaProt	LLR -9.10	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 32 kb · p 0.0075 · regional, not allelic
Overall
CADD	25.5	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 0.0201% East Asian · 9/44,856 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.00502% 81/1,613,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.056%	1,786
East Asiangrpmax	0.0201%	4,984
Middle Eastern	0.0165%	6,062
South Asian	0.00989%	10,116
African / African-American	0.00934%	10,706
European (non-Finnish)	0.00169%	58,999

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: BTBD1
Protein: p.Arg320Gln
Coding: c.959G>A
MANE Select: NM_025238
dbSNP: rs375845805
Type: single nucleotide variant
Location: chr15:83030232 (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-arg320gln (accessed [today's date]).

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