Is ATM p.Pro1069Ser (c.3205C>T) pathogenic?

ATM p.Pro1069Ser (c.3205C>T) is classified Likely benign in ATM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). AlphaMissense: likely benign (0.1175); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Pro1069Ser (c.3205C>T)?

ATM p.Pro1069Ser (c.3205C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ATM p.Pro1069Ser (c.3205C>T) in the general population?

ATM p.Pro1069Ser (c.3205C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ATM p.Pro1069Ser (c.3205C>T)?

AlphaMissense predicts likely benign (score 0.1175) — an in-silico prediction, not a clinical call.

ATM p.Pro1069Ser

c.3205C>T · rs751714261 · VCV3232903

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1175 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1175	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.32, phastCons 0.53
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.75 · regional, not allelic
Overall
CADD	10.06	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,924 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,710 alleles · very rare

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: ATM
Protein: p.Pro1069Ser
Coding: c.3205C>T
MANE Select: NM_000051
dbSNP: rs751714261
Type: single nucleotide variant
Location: chr11:108272773 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1069: a UniProt-annotated variant site (in at); a β-strand; 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

Similar variants

ATM p.Pro1069fs Pathogenic/Likely pathogenic ★★ same residue
ATM p.Pro1069Ala Uncertain significance ★★ ⚠ same residue
ATM p.Pro1069Leu Uncertain significance ★ same residue
ATM p.Pro1069Thr Uncertain significance ★ ⚠ same residue
ATM p.Pro1069= Likely benign ★ 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

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-pro1069ser (accessed [today's date]).

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