Is DAPP1 p.Ser12Thr (c.35G>C) pathogenic?

DAPP1 p.Ser12Thr (c.35G>C) is classified Uncertain significance in DAPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: likely benign (0.0732); Very rare (popmax 0.00673%, amr).

How common is DAPP1 p.Ser12Thr (c.35G>C) in the general population?

DAPP1 p.Ser12Thr (c.35G>C) is very rare (popmax 0.00673%, amr) (gnomAD).

What do computational predictors say about DAPP1 p.Ser12Thr (c.35G>C)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

DAPP1 p.Ser12Thr

c.35G>C · rs1266285786 · VCV2260403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00673%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.29, phastCons 0.99
Regional constraint	o/e 0.70	unconstrained · MANE · 51 kb · p 3.8e-08 · regional, not allelic
Overall
CADD	17.83	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00673% Admixed American · 4/59,436 alleles

Filtering AF 0.00227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00087% 14/1,609,228 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00673%	14,859
African / African-American	0.00134%	74,842
European (non-Finnish)	0.000764%	130,886

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: DAPP1
Protein: p.Ser12Thr
Coding: c.35G>C
MANE Select: NM_014395
dbSNP: rs1266285786
Type: single nucleotide variant
Location: chr4:99816948 (GRCh38)
Gene constraint: LOEUF 0.905 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.43 · 2 PDB
Residue 12: the 'disordered' region

Full DAPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DAPP1 p.Ala215Thr Uncertain significance ★ ⚠ same type
DAPP1 p.Arg143Gln Uncertain significance ★ ⚠ same type
DAPP1 p.Arg255His Uncertain significance ★ ⚠ same type
DAPP1 p.Arg262Ile Uncertain significance ★ ⚠ same type
DAPP1 p.Arg275Trp Uncertain significance ★ ⚠ same type
DAPP1 p.Asp15Asn Uncertain significance ★ ⚠ same type
DAPP1 p.Asp15Glu Uncertain significance ★ ⚠ same type
DAPP1 p.Asp219Asn 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/dapp1-p-ser12thr (accessed [today's date]).

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