Is ATRIP p.Leu690Phe (c.2068C>T) pathogenic?

ATRIP p.Leu690Phe (c.2068C>T) is classified Uncertain significance in ATRIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: ambiguous (0.3954); Very rare (popmax 0.00951%, nfe).

How common is ATRIP p.Leu690Phe (c.2068C>T) in the general population?

ATRIP p.Leu690Phe (c.2068C>T) is very rare (popmax 0.00951%, nfe) (gnomAD).

What do computational predictors say about ATRIP p.Leu690Phe (c.2068C>T)?

AlphaMissense predicts ambiguous (score 0.3954) — an in-silico prediction, not a clinical call.

ATRIP p.Leu690Phe

c.2068C>T · rs146364953 · VCV2340760

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00951%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3954	ambiguous
REVEL	0.126	moderately benign-leaning
SaProt	LLR -11.64	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 19 kb · p 0.089 · regional, not allelic
Overall
CADD	22.7	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 0.00951% European (non-Finnish) · 112/1,178,122 alleles

Filtering AF 0.00805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00753%

Overall 0.00738% 119/1,611,384 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00951%	10,519
Admixed American	0.00501%	19,976
Remaining individualsnot grpmax-eligible	0.00481%	20,789
African / African-American	0.00134%	74,898

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.Leu690Phe
Coding: c.2068C>T
MANE Select: NM_130384
dbSNP: rs146364953
Type: single nucleotide variant
Location: chr3:48464843 (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

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
ATRIP p.Ala173Val Uncertain significance ★★ ⚠ same type
ATRIP p.Ala374Thr 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-leu690phe (accessed [today's date]).

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