Is DNTTIP2 p.Gly574Asp (c.1721G>A) pathogenic?

DNTTIP2 p.Gly574Asp (c.1721G>A) is classified Uncertain significance in DNTTIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely pathogenic (0.7742); Very rare (popmax 0.00401%, afr).

How common is DNTTIP2 p.Gly574Asp (c.1721G>A) in the general population?

DNTTIP2 p.Gly574Asp (c.1721G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about DNTTIP2 p.Gly574Asp (c.1721G>A)?

AlphaMissense predicts likely pathogenic (score 0.7742) — an in-silico prediction, not a clinical call.

DNTTIP2 p.Gly574Asp

c.1721G>A · VCV3273269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7742	likely pathogenic
REVEL	0.406	indeterminate
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 9,294 bp · p 0.47 · regional, not allelic
Overall
CADD	25.6	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 0.00401% African / African-American · 3/74,860 alleles

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

Overall 0.000434% 7/1,613,198 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,953
Admixed American	0.00334%	29,981
European (non-Finnish)	0.00017%	589,852

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: DNTTIP2
Protein: p.Gly574Asp
Coding: c.1721G>A
MANE Select: NM_014597
Type: single nucleotide variant
Location: chr1:93875730 (GRCh38)
Gene constraint: LOEUF 0.976 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.47 · 3 PDB
Residue 574: the 'tdbr region; mediates interaction with dntt' region

Full DNTTIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNTTIP2 p.Ala11Thr Uncertain significance ★ ⚠ same type
DNTTIP2 p.Ala347Val Uncertain significance ★ ⚠ same type
DNTTIP2 p.Ala358Pro Uncertain significance ★ ⚠ same type
DNTTIP2 p.Ala43Ser Uncertain significance ★ ⚠ same type
DNTTIP2 p.Ala43Thr Uncertain significance ★ ⚠ same type
DNTTIP2 p.Ala43Val Uncertain significance ★ ⚠ same type
DNTTIP2 p.Ala511Val Uncertain significance ★ ⚠ same type
DNTTIP2 p.Ala554Val 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/dnttip2-p-gly574asp (accessed [today's date]).

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