Is ATM p.Pro2222Ser (c.6664C>T) pathogenic?

ATM p.Pro2222Ser (c.6664C>T) is classified Uncertain significance in ATM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-21). AlphaMissense: ambiguous (0.3557); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Pro2222Ser (c.6664C>T)?

ATM p.Pro2222Ser (c.6664C>T) is associated with hereditary neoplastic syndrome, ataxia telangiectasia (ClinVar).

How common is ATM p.Pro2222Ser (c.6664C>T) in the general population?

ATM p.Pro2222Ser (c.6664C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATM p.Pro2222Ser (c.6664C>T)?

AlphaMissense predicts ambiguous (score 0.3557) — an in-silico prediction, not a clinical call.

ATM p.Pro2222Ser

c.6664C>T · rs2085561331 · VCV1754749

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3557 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3557	ambiguous
REVEL	0.489	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 60 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	25.4	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

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.Pro2222Ser
Coding: c.6664C>T
MANE Select: NM_000051
dbSNP: rs2085561331
Type: single nucleotide variant
Location: chr11:108325401 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2222: a UniProt-annotated variant site (in at; uncertain significance; reduces protein abundance); a UniProt-annotated variant site (in at); the fat domain; a UniProt-annotated variant site (in at; uncertain significance); an α-helix; a UniProt-annotated variant site (in at; uncertain significance; increases protein abundance)

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.Pro2222Arg Uncertain significance ★★ same residue
ATM p.Pro2222Leu Uncertain significance ★★ same residue
ATM p.Pro2222Ala Uncertain significance ★ same residue
ATM p.Pro2222= Likely benign ★ same residue
ATM p.Pro2222fs Pathogenic ★ 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-pro2222ser (accessed [today's date]).

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