Is ATRIP p.Arg721Trp (c.2161C>T) pathogenic?

ATRIP p.Arg721Trp (c.2161C>T) is classified Uncertain significance in ATRIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.7375); Very rare (popmax 0.00133%, afr).

How common is ATRIP p.Arg721Trp (c.2161C>T) in the general population?

ATRIP p.Arg721Trp (c.2161C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ATRIP p.Arg721Trp (c.2161C>T)?

AlphaMissense predicts likely pathogenic (score 0.7375) — an in-silico prediction, not a clinical call.

ATRIP p.Arg721Trp

c.2161C>T · rs752926281 · VCV2240751

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7375	likely pathogenic · top 10% in ATRIP
REVEL	0.633	indeterminate
SaProt	LLR -12.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.35, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 19 kb · p 0.089 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,942 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,942
South Asian	0.0011%	91,088
European (non-Finnish)	0.00102%	98,337

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: ATRIP
Protein: p.Arg721Trp
Coding: c.2161C>T
MANE Select: NM_130384
dbSNP: rs752926281
Type: single nucleotide variant
Location: chr3:48464936 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.10 · 24 PDB

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

Similar variants

ATRIP p.Arg721= Likely benign ★★ same residue
ATRIP p.Arg721Gln Uncertain significance ★ ⚠ same residue
TREX1 p.Arg114His Pathogenic/Likely pathogenic ★★ ⚠ same type
TREX1 p.Arg164Ter Pathogenic/Likely pathogenic ★★ same type
TREX1 p.Asp18Asn Pathogenic ★★ same type
TREX1 p.Asp200His Likely pathogenic ★★ same type
TREX1 p.Gln135Ter Pathogenic/Likely pathogenic ★★ same type
ATRIP p.Ala119Thr 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/atrip-p-arg721trp (accessed [today's date]).

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