Is BPTF p.Arg649Gln (c.1946G>A) pathogenic?

BPTF p.Arg649Gln (c.1946G>A) is classified Uncertain significance in BPTF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.7288); Very rare (popmax 0.00144%, nfe).

How common is BPTF p.Arg649Gln (c.1946G>A) in the general population?

BPTF p.Arg649Gln (c.1946G>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about BPTF p.Arg649Gln (c.1946G>A)?

AlphaMissense predicts likely pathogenic (score 0.7288) — an in-silico prediction, not a clinical call.

BPTF p.Arg649Gln

c.1946G>A · rs773926002 · VCV2878029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Computational evidence

Protein change
AlphaMissense	0.7288	likely pathogenic
REVEL	0.336	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 37 kb · p 0.31 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R775Q vs ClinVar R649Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,526 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00144% 21/1,460,478 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,818
Finnishnot grpmax-eligible	0.00156%	64,014
European (non-Finnish)grpmax	0.00144%	69,384

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: BPTF
Protein: p.Arg649Gln
Coding: c.1946G>A
MANE Select: NM_182641
dbSNP: rs773926002
Type: single nucleotide variant
Location: chr17:67891925 (GRCh38)
Gene constraint: LOEUF 0.09 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 649: the 'disordered' region; the 'interaction with keap1' region

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

Similar variants

BPTF p.Arg1322Ter Pathogenic/Likely pathogenic ★★ same type
BPTF p.Arg1738Ter Pathogenic/Likely pathogenic ★★ same type
BPTF p.Arg2858Ter Pathogenic ★★ same type
BPTF p.Arg841Ter Pathogenic ★★ same type
BPTF c.1864+562A>T Uncertain significance ★★ same type
BPTF c.1865-5651C>G Uncertain significance ★★ ⚠ same type
BPTF p.Ala1197Val Uncertain significance ★★ ⚠ same type
BPTF p.Ala1252Val 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/bptf-p-arg649gln (accessed [today's date]).

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