Is ATM p.Phe239Ser (c.716T>C) pathogenic?

ATM p.Phe239Ser (c.716T>C) is classified Uncertain significance in ATM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-09). AlphaMissense: ambiguous (0.3436); Ultra-rare (popmax 0.0107%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Phe239Ser (c.716T>C)?

ATM p.Phe239Ser (c.716T>C) is associated with hereditary neoplastic syndrome, ataxia telangiectasia, hereditary breast carcinoma (ClinVar).

How common is ATM p.Phe239Ser (c.716T>C) in the general population?

ATM p.Phe239Ser (c.716T>C) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about ATM p.Phe239Ser (c.716T>C)?

AlphaMissense predicts ambiguous (score 0.3436) — an in-silico prediction, not a clinical call.

ATM p.Phe239Ser

c.716T>C · rs143198946 · VCV187667

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3436 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3436	ambiguous
REVEL	0.31	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.75 · regional, not allelic
Overall
CADD	24.4	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 0.0107% African / African-American · 8/74,908 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000558% 9/1,613,826 alleles · ultra-rare exomes 2/1,461,632 · genomes 7/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,363
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Phe239Ser
Coding: c.716T>C
MANE Select: NM_000051
dbSNP: rs143198946
Type: single nucleotide variant
Location: chr11:108244841 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 239: 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

Also linked: ataxia telangiectasia hereditary breast carcinoma

Similar variants

ATM p.Phe239= Benign/Likely benign ★★ same residue
ATM p.Phe239Cys Uncertain significance ★ same residue
ATM p.Phe239Leu Uncertain significance ★ ⚠ same residue
ATM p.Phe239fs 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
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-phe239ser (accessed [today's date]).

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