Is BPTF p.Thr2125Met (c.6374C>T) pathogenic?

BPTF p.Thr2125Met (c.6374C>T) is classified Benign/Likely benign in BPTF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.1035); Rare (popmax 0.297%, mid).

How common is BPTF p.Thr2125Met (c.6374C>T) in the general population?

BPTF p.Thr2125Met (c.6374C>T) is rare (popmax 0.297%, mid) (gnomAD).

What do computational predictors say about BPTF p.Thr2125Met (c.6374C>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

BPTF p.Thr2125Met

c.6374C>T · rs138207871 · VCV2055197

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.297%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.193	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 0.8
Regional constraint	o/e 0.90	unconstrained · MANE · 18 kb · p 0.012 · regional, not allelic
Overall
CADD	24.7	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 T2251M vs ClinVar T2125M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.297% Middle Eastern · 18/6,062 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.0256% 413/1,614,126 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.777%	129
Middle Easterngrpmax	0.297%	337
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Admixed American	0.065%	1,538
South Asian	0.00659%	15,179
European (non-Finnish)	0.00636%	15,734
African / African-American	0.00267%	37,519
East Asian	0.00223%	44,880

Ashkenazi Jewish 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.Thr2125Met
Coding: c.6374C>T
MANE Select: NM_182641
dbSNP: rs138207871
Type: single nucleotide variant
Location: chr17:67940553 (GRCh38)
Gene constraint: LOEUF 0.09 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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

Similar variants

BPTF p.Thr2125Ser Uncertain significance ★ ⚠ same residue
BPTF p.Thr2125= Likely benign ★ same residue
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

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-thr2125met (accessed [today's date]).

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