Is ATRIP p.Leu542Phe (c.1624C>T) pathogenic?

ATRIP p.Leu542Phe (c.1624C>T) is classified Uncertain significance in ATRIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-20). AlphaMissense: ambiguous (0.3937); Ultra-rare (popmax 0.033%, mid).

How common is ATRIP p.Leu542Phe (c.1624C>T) in the general population?

ATRIP p.Leu542Phe (c.1624C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about ATRIP p.Leu542Phe (c.1624C>T)?

AlphaMissense predicts ambiguous (score 0.3937) — an in-silico prediction, not a clinical call.

ATRIP p.Leu542Phe

c.1624C>T · rs768083756 · VCV2185167

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3937 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Computational evidence

Protein change
AlphaMissense	0.3937	ambiguous
REVEL	0.352	indeterminate
SaProt	LLR -10.87	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.77, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 19 kb · p 0.089 · regional, not allelic
Overall
CADD	24.3	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.0052% 84/1,614,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.00627%	15,945
Admixed American	0.005%	20,006
African / African-American	0.00133%	75,068

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.Leu542Phe
Coding: c.1624C>T
MANE Select: NM_130384
dbSNP: rs768083756
Type: single nucleotide variant
Location: chr3:48460678 (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.Leu542= Likely benign ★★ same residue
ATRIP p.Leu542His Uncertain significance ★ ⚠ same residue
ATRIP p.Leu542Pro 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

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-leu542phe (accessed [today's date]).

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