Is BPTF p.Lys660Arg (c.1979A>G) pathogenic?

BPTF p.Lys660Arg (c.1979A>G) is classified Uncertain significance in BPTF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.192); Ultra-rare (popmax 0.0165%, mid); Associated with neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

What condition is associated with BPTF p.Lys660Arg (c.1979A>G)?

BPTF p.Lys660Arg (c.1979A>G) is associated with neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (ClinVar).

How common is BPTF p.Lys660Arg (c.1979A>G) in the general population?

BPTF p.Lys660Arg (c.1979A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BPTF p.Lys660Arg (c.1979A>G)?

AlphaMissense predicts likely benign (score 0.192) — an in-silico prediction, not a clinical call.

BPTF p.Lys660Arg

c.1979A>G · rs2061144291 · VCV915428

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

neurodevelopmental disorder with dysmorphic facies and distal limb anomalies

Computational evidence

Protein change
AlphaMissense	0.192	likely benign
REVEL	0.196	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 6, phastCons 1
Regional constraint	o/e 0.23	constrained · MANE · 55 bp · p 0.00029 · regional, not allelic
Overall
CADD	26.5	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K786R vs ClinVar K660R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 0.000124% 2/1,612,804 alleles · ultra-rare exomes 2/1,460,464 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	8.48e-05%	1,179,518

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.Lys660Arg
Coding: c.1979A>G
MANE Select: NM_182641
dbSNP: rs2061144291
Type: single nucleotide variant
Location: chr17:67891958 (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

Disease context

neurodevelopmental disorder with dysmorphic facies and distal limb anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BPTF p.Arg1322Ter Pathogenic/Likely pathogenic ★★ same condition
BPTF p.Arg2858Ter Pathogenic ★★ same condition
BPTF p.Arg2058Cys Uncertain significance ★★ same condition
BPTF p.Arg2139His Uncertain significance ★★ ⚠ same condition
BPTF p.Arg2858Gln Uncertain significance ★★ ⚠ same condition
BPTF p.Arg542Gln Uncertain significance ★★ same condition
BPTF p.Arg68Ser Uncertain significance ★★ ⚠ same condition
BPTF p.Asn452Ser 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/bptf-p-lys660arg (accessed [today's date]).

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