Is DNTTIP2 p.Ser722Cys (c.2165C>G) pathogenic?

DNTTIP2 p.Ser722Cys (c.2165C>G) is classified Uncertain significance in DNTTIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: ambiguous (0.5537); Very rare (popmax 0.00403%, nfe).

How common is DNTTIP2 p.Ser722Cys (c.2165C>G) in the general population?

DNTTIP2 p.Ser722Cys (c.2165C>G) is very rare (popmax 0.00403%, nfe) (gnomAD).

What do computational predictors say about DNTTIP2 p.Ser722Cys (c.2165C>G)?

AlphaMissense predicts ambiguous (score 0.5537) — an in-silico prediction, not a clinical call.

DNTTIP2 p.Ser722Cys

c.2165C>G · rs750306219 · VCV2475722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00403%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5537	ambiguous
REVEL	0.366	indeterminate
SaProt	LLR -11.17	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 9,294 bp · p 0.47 · regional, not allelic
Overall
CADD	29.6	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 0.00403% European (non-Finnish) · 46/1,141,324 alleles

Filtering AF 0.00309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00336% 52/1,546,428 alleles · very rare exomes 48/1,394,420 · genomes 4/152,008 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00841%	11,886
European (non-Finnish)grpmax	0.00403%	24,811
African / African-American	0.00136%	73,698

Remaining individuals 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: DNTTIP2
Protein: p.Ser722Cys
Coding: c.2165C>G
MANE Select: NM_014597
dbSNP: rs750306219
Type: single nucleotide variant
Location: chr1:93870695 (GRCh38)
Gene constraint: LOEUF 0.976 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.47 · 3 PDB
Residue 722: an α-helix

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-ser722cys (accessed [today's date]).

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