Is ATM p.Ser333Phe (c.998C>T) pathogenic?

ATM p.Ser333Phe (c.998C>T) is classified Conflicting classifications of pathogenicity in ATM (ClinVar, Conflicting submitters, 34 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.3118); Rare (popmax 0.382%, amr); Associated with ATM-related cancer predisposition.

What condition is associated with ATM p.Ser333Phe (c.998C>T)?

ATM p.Ser333Phe (c.998C>T) is associated with ATM-related cancer predisposition, hereditary breast ovarian cancer syndrome, ataxia telangiectasia (ClinVar).

How common is ATM p.Ser333Phe (c.998C>T) in the general population?

ATM p.Ser333Phe (c.998C>T) is rare (popmax 0.382%, amr) (gnomAD).

What do computational predictors say about ATM p.Ser333Phe (c.998C>T)?

AlphaMissense predicts likely benign (score 0.3118) — an in-silico prediction, not a clinical call.

ATM p.Ser333Phe

c.998C>T · rs28904919 · VCV127471

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 34 submitters

AlphaMissense

likely benign

0.3118 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.382%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

ATM-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.3118	likely benign
REVEL	0.073	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 3.9	GERP 0.73, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.75 · regional, not allelic
Overall
CADD	23.9	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 0.382% Admixed American · 229/60,010 alleles

Filtering AF 0.341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.325%

Overall 0.143% 2,305/1,613,876 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.382%	262
Finnishnot grpmax-eligible	0.381%	262
European (non-Finnish)	0.146%	684
Remaining individualsnot grpmax-eligible	0.141%	710
Middle Eastern	0.033%	3,027
African / African-American	0.0213%	4,688
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
East Asian	0.00223%	44,814

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.Ser333Phe
Coding: c.998C>T
MANE Select: NM_000051
dbSNP: rs28904919
Type: single nucleotide variant
Location: chr11:108247060 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 333: a UniProt-annotated variant site (in at); a UniProt-annotated variant site (in)

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

Disease context

Also linked: hereditary breast ovarian cancer syndrome ataxia telangiectasia hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

ATM p.Ser333= Benign/Likely benign ★★ same residue
ATM p.Ser333Cys Uncertain significance ★ ⚠ same residue
ATM p.Ser333Thr Uncertain significance ★ ⚠ same residue
ATM c.1607+1G>T Pathogenic ★★★ same condition
ATM c.2251-2A>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-ser333phe (accessed [today's date]).

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