Is ATM p.Arg221Ter (c.661A>T) pathogenic?

ATM p.Arg221Ter (c.661A>T) is classified Likely pathogenic in ATM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Arg221Ter (c.661A>T)?

ATM p.Arg221Ter (c.661A>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ATM p.Arg221Ter (c.661A>T) in the general population?

ATM p.Arg221Ter (c.661A>T) is absent from gnomAD v4.1 (gnomAD).

ATM p.Arg221Ter

c.661A>T · rs2135227474 · VCV1754508

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 6 of 63
Splicing
SpliceAI	Δ0.58	donor loss · deltas
Pangolin	Δ0.54	loss · gain 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9	GERP 1.2, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Arg221Ter
Coding: c.661A>T
MANE Select: NM_000051
dbSNP: rs2135227474
Type: single nucleotide variant
Location: chr11:108244117 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 221: a UniProt-annotated variant site (in at); an α-helix

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.Arg221Gly Uncertain significance ★★ same residue
ATM p.Arg221Lys Uncertain significance ★★ ⚠ same residue
ATM p.Arg221Ser Uncertain significance ★★ ⚠ same residue
ATM p.Arg221= 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
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-arg221ter (accessed [today's date]).

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