Is ATRIP p.Gln681His (c.2043G>C) pathogenic?

ATRIP p.Gln681His (c.2043G>C) is classified Uncertain significance in ATRIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.2595); Rare (popmax 0.197%, afr).

How common is ATRIP p.Gln681His (c.2043G>C) in the general population?

ATRIP p.Gln681His (c.2043G>C) is rare (popmax 0.197%, afr) (gnomAD).

What do computational predictors say about ATRIP p.Gln681His (c.2043G>C)?

AlphaMissense predicts likely benign (score 0.2595) — an in-silico prediction, not a clinical call.

ATRIP p.Gln681His

c.2043G>C · rs113448339 · VCV2084884

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2595 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2595	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.68	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 0.54	GERP -2.2, phastCons 0.99
Regional constraint	o/e 0.95	unconstrained · MANE · 19 kb · p 0.089 · regional, not allelic
Overall
CADD	15.27	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 0.197% African / African-American · 148/75,070 alleles

Filtering AF 0.171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.161%

Overall 0.0121% 196/1,614,226 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.197%	507
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.032%	3,125
South Asian	0.00988%	10,121
Admixed American	0.005%	20,011
Finnishnot grpmax-eligible	0.00156%	64,030
European (non-Finnish)	0.000847%	118,003

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.Gln681His
Coding: c.2043G>C
MANE Select: NM_130384
dbSNP: rs113448339
Type: single nucleotide variant
Location: chr3:48464650 (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.Gln681Pro Uncertain significance ★ ⚠ same residue
ATRIP p.Gln681= Likely benign ★ 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-gln681his (accessed [today's date]).

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