Is ATR p.Phe153Leu (c.457T>C) pathogenic?

ATR p.Phe153Leu (c.457T>C) is classified Uncertain significance in ATR (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.5504); Ultra-rare (popmax 0.0154%, sas); Associated with Seckel syndrome 1.

What condition is associated with ATR p.Phe153Leu (c.457T>C)?

ATR p.Phe153Leu (c.457T>C) is associated with Seckel syndrome 1 (ClinVar).

How common is ATR p.Phe153Leu (c.457T>C) in the general population?

ATR p.Phe153Leu (c.457T>C) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about ATR p.Phe153Leu (c.457T>C)?

AlphaMissense predicts ambiguous (score 0.5504) — an in-silico prediction, not a clinical call.

ATR p.Phe153Leu

c.457T>C · rs201181535 · VCV3250417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5504 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Seckel syndrome 1

Computational evidence

Protein change
AlphaMissense	0.5504	ambiguous
REVEL	0.106	moderately benign-leaning
SaProt	LLR -3.60	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.2, phastCons 1
Overall
CADD	16.42	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 0.0154% South Asian · 14/90,676 alleles

Filtering AF 0.00933% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00738%

Overall 0.00167% 27/1,613,184 alleles · ultra-rare exomes 25/1,460,864 · genomes 2/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,477
Finnishnot grpmax-eligible	0.0109%	9,147
Remaining individualsnot grpmax-eligible	0.0096%	10,412

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: ATR
Protein: p.Phe153Leu
Coding: c.457T>C
MANE Select: NM_001184
dbSNP: rs201181535
Type: single nucleotide variant
Location: chr3:142562945 (GRCh38)
Structure: AlphaFold pLDDT 72.76 · 5 PDB
Residue 153: an α-helix; the vwfa domain

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

Disease context

Seckel syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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ATR p.Arg1015Ter Pathogenic/Likely pathogenic ★★ same condition
ATR p.Arg1653Ter Pathogenic/Likely pathogenic ★★ same condition
ATR p.Arg1951Ter Pathogenic ★★ same condition
ATR p.Arg2533Ter Pathogenic/Likely pathogenic ★★ same condition
ATR p.Gln1137Ter Pathogenic ★★ same condition

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/atr-p-phe153leu (accessed [today's date]).

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