Is ATM p.Gly1663Ser (c.4987G>A) pathogenic?

ATM p.Gly1663Ser (c.4987G>A) is classified Uncertain significance in ATM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-23). AlphaMissense: likely benign (0.1199); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Gly1663Ser (c.4987G>A)?

ATM p.Gly1663Ser (c.4987G>A) is associated with hereditary neoplastic syndrome, ataxia telangiectasia, hereditary breast carcinoma (ClinVar).

How common is ATM p.Gly1663Ser (c.4987G>A) in the general population?

ATM p.Gly1663Ser (c.4987G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ATM p.Gly1663Ser (c.4987G>A)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

ATM p.Gly1663Ser

c.4987G>A · rs1346404008 · VCV1385497

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.205	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.25	donor loss · deltas
Pangolin	Δ0.25	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 60 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	24.3	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,028 alleles

Overall 6.84e-05% 1/1,461,584 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.Gly1663Ser
Coding: c.4987G>A
MANE Select: NM_000051
dbSNP: rs1346404008
Type: single nucleotide variant
Location: chr11:108297364 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1663: a UniProt-annotated variant site (in at); a UniProt-annotated variant site (in at; uncertain significance); a β-strand; 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 hereditary breast carcinoma

Similar variants

ATM p.Gly1663Asp Uncertain significance ★★ ⚠ same residue
ATM p.Gly1663Cys Uncertain significance ★ same residue
ATM p.Gly1663Val Uncertain significance ★ same residue
ATM p.Gly1663= Likely benign ★ same residue
ATM p.Gly1663fs Pathogenic ★ same residue
ATM p.Gly1663Ala Uncertain significance ★ ⚠ same residue
ATM c.1607+1G>T Pathogenic ★★★ same condition
ATM c.2251-4A>G 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-gly1663ser (accessed [today's date]).

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