Is KPTN p.Pro168= (c.504G>A) pathogenic?

KPTN p.Pro168= (c.504G>A) is classified Benign in KPTN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Low-frequency (popmax 2.77%, nfe); Associated with macrocephaly-developmental delay syndrome.

What condition is associated with KPTN p.Pro168= (c.504G>A)?

KPTN p.Pro168= (c.504G>A) is associated with macrocephaly-developmental delay syndrome (ClinVar).

How common is KPTN p.Pro168= (c.504G>A) in the general population?

KPTN p.Pro168= (c.504G>A) is low-frequency (popmax 2.77%, nfe) (gnomAD).

KPTN p.Pro168=

c.504G>A · rs61743291 · VCV474857

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.77%, nfe)

Conditions

macrocephaly-developmental delay syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -4.1
Overall
CADD	0.248	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.77% European (non-Finnish) · 32,566/1,173,684 alleles

Filtering AF 2.75% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.74%

Overall 2.48% 39,658/1,601,960 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	6.96%	14
European (non-Finnish)grpmax	2.77%	36
Remaining individualsnot grpmax-eligible	2%	50
Admixed American	0.976%	102
Amishnot grpmax-eligible	0.658%	152
Ashkenazi Jewishnot grpmax-eligible	0.579%	173
South Asian	0.446%	224
African / African-American	0.388%	258
Middle Eastern	0.38%	263
East Asian	0.00225%	44,402

Finnish 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: KPTN
Protein: p.Pro168=
Coding: c.504G>A
MANE Select: NM_007059
dbSNP: rs61743291
Type: single nucleotide variant
Location: chr19:47480979 (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.Pro168Leu Uncertain significance ★ ⚠ same residue
KPTN p.Pro168Ser 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-pro168 (accessed [today's date]).

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