Is DAPK1 p.Ser469Pro (c.1405T>C) pathogenic?

DAPK1 p.Ser469Pro (c.1405T>C) is classified Uncertain significance in DAPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.6635); Very rare (popmax 0.004%, afr).

How common is DAPK1 p.Ser469Pro (c.1405T>C) in the general population?

DAPK1 p.Ser469Pro (c.1405T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about DAPK1 p.Ser469Pro (c.1405T>C)?

AlphaMissense predicts likely pathogenic (score 0.6635) — an in-silico prediction, not a clinical call.

DAPK1 p.Ser469Pro

c.1405T>C · VCV4658452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6635	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -10.58	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 151 kb · p 1.5e-16 · regional, not allelic
Overall
CADD	23.7	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 0.004% African / African-American · 3/74,944 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,068 alleles · very rare

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: DAPK1
Protein: p.Ser469Pro
Coding: c.1405T>C
MANE Select: NM_004938
Type: single nucleotide variant
Location: chr9:87648856 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.74 · 79 PDB

Full DAPK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DAPK1 c.1131+9C>T Benign ★★ same type
DAPK1 c.1231-6C>G Benign ★★ same type
DAPK1 c.285-6T>C Benign ★★ same type
DAPK1 c.919-10T>A Benign ★★ same type
DAPK1 c.919-9A>T Likely benign ★★ same type
DAPK1 p.Asn1347= Benign ★★ same type
DAPK1 p.Gln122= Benign ★★ same type
DAPK1 p.Gly1348Val Likely benign ★★ 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/dapk1-p-ser469pro (accessed [today's date]).

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