Is KPTN p.Arg288Pro (c.863G>C) pathogenic?

KPTN p.Arg288Pro (c.863G>C) is classified Likely pathogenic in KPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). AlphaMissense: likely pathogenic (0.8667); Very rare (popmax 8.49e-05%, nfe); Associated with macrocephaly-developmental delay syndrome.

What condition is associated with KPTN p.Arg288Pro (c.863G>C)?

KPTN p.Arg288Pro (c.863G>C) is associated with macrocephaly-developmental delay syndrome (ClinVar).

How common is KPTN p.Arg288Pro (c.863G>C) in the general population?

KPTN p.Arg288Pro (c.863G>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about KPTN p.Arg288Pro (c.863G>C)?

AlphaMissense predicts likely pathogenic (score 0.8667) — an in-silico prediction, not a clinical call.

KPTN p.Arg288Pro

c.863G>C · rs772378754 · VCV1703138

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

macrocephaly-developmental delay syndrome

Computational evidence

Protein change
AlphaMissense	0.8667	likely pathogenic ✓ concordant with ClinVar
REVEL	0.238	benign-leaning
SaProt	LLR -13.57	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.82	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,741 bp · p 0.049 · regional, not allelic
Overall
CADD	35.0	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 8.49e-05% European (non-Finnish) · 1/1,178,220 alleles

Overall 6.2e-05% 1/1,611,896 alleles · very rare exomes 0/1,459,736 · genomes 1/152,160 · joint denominator

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: KPTN
Protein: p.Arg288Pro
Coding: c.863G>C
MANE Select: NM_007059
dbSNP: rs772378754
Type: single nucleotide variant
Location: chr19:47477706 (GRCh38)
Gene constraint: LOEUF 0.988 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.56 · 8 PDB

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

Disease context

macrocephaly-developmental delay syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KPTN p.Arg288Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
KPTN p.Arg288Trp Uncertain significance ★ ⚠ same residue
KPTN p.Ser259Ter Pathogenic ★★ same condition
KPTN c.1183-3C>G Uncertain significance ★★ same condition
KPTN p.Ala260Asp Uncertain significance ★★ ⚠ same condition
KPTN p.Ala261Thr Uncertain significance ★★ ⚠ same condition
KPTN p.Ala329Pro Uncertain significance ★★ ⚠ same condition
KPTN p.Ala35Thr 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/kptn-p-arg288pro (accessed [today's date]).

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