Is ATM p.Pro596Ala (c.1786C>G) pathogenic?

ATM p.Pro596Ala (c.1786C>G) is classified Uncertain significance in ATM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-21). AlphaMissense: likely benign (0.1046); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Pro596Ala (c.1786C>G)?

ATM p.Pro596Ala (c.1786C>G) is associated with hereditary neoplastic syndrome, ataxia telangiectasia (ClinVar).

How common is ATM p.Pro596Ala (c.1786C>G) in the general population?

ATM p.Pro596Ala (c.1786C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATM p.Pro596Ala (c.1786C>G)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

ATM p.Pro596Ala

c.1786C>G · rs2135344182 · VCV2120683

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.125	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.9, phastCons 0.95
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.75 · regional, not allelic
Overall
CADD	14.89	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ATM
Protein: p.Pro596Ala
Coding: c.1786C>G
MANE Select: NM_000051
dbSNP: rs2135344182
Type: single nucleotide variant
Location: chr11:108252015 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 596: a UniProt-annotated variant site (in at); a UniProt-annotated variant site (in at; uncertain significance)

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

Disease context

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

Also linked: ataxia telangiectasia

Similar variants

ATM p.Pro596Leu Uncertain significance ★★ ⚠ same residue
ATM p.Pro596= Benign/Likely benign ★★ same residue
ATM p.Pro596Thr Uncertain significance ★ ⚠ same residue
ATM p.Pro596Arg Uncertain significance ★ ⚠ same residue
ATM c.1607+1G>T Pathogenic ★★★ same condition
ATM c.2251-4A>G Likely pathogenic ★★★ same condition
ATM c.2466+5G>C Likely pathogenic ★★★ same condition
ATM c.3078-1G>A 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/atm-p-pro596ala (accessed [today's date]).

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