Is ATM p.Pro424= (c.1272T>C) pathogenic?

ATM p.Pro424= (c.1272T>C) is classified Conflicting classifications of pathogenicity in ATM (ClinVar, Conflicting submitters, 25 submitters; last evaluated 2026-02-04). Rare (popmax 0.593%, mid); Associated with Breast and/or ovarian cancer.

What condition is associated with ATM p.Pro424= (c.1272T>C)?

ATM p.Pro424= (c.1272T>C) is associated with Breast and/or ovarian cancer, breast cancer, ataxia telangiectasia (ClinVar).

How common is ATM p.Pro424= (c.1272T>C) in the general population?

ATM p.Pro424= (c.1272T>C) is rare (popmax 0.593%, mid) (gnomAD).

ATM p.Pro424=

c.1272T>C · rs35578748 · VCV135732

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 25 submitters

gnomAD v4.1

Rare

rare (popmax 0.593%, mid)

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -3.2, phastCons 0.98
Overall
CADD	8.791	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.593% Middle Eastern · 36/6,068 alleles

Filtering AF 0.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.388%

Overall 0.024% 387/1,610,944 alleles · rare exomes 358/1,459,396 · genomes 29/151,548 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.593%	169
Remaining individualsnot grpmax-eligible	0.0609%	1,643
South Asian	0.0264%	3,791
European (non-Finnish)	0.0225%	4,435
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,932
Admixed American	0.0134%	7,480
African / African-American	0.012%	8,301

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.Pro424=
Coding: c.1272T>C
MANE Select: NM_000051
dbSNP: rs35578748
Type: single nucleotide variant
Location: chr11:108250737 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 424: a UniProt-annotated variant site (in at); an α-helix; a UniProt-annotated variant site (in at; uncertain significance)

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

ATM p.Pro424Ala Uncertain significance ★★ ⚠ same residue
ATM p.Pro424Leu Uncertain significance ★★ same residue
ATM p.Pro424His Conflicting classifications of pathogenicity ★ same residue
ATM p.Pro424Ser Uncertain significance ★ ⚠ same residue
ATM p.Pro424Thr Uncertain significance ★ ⚠ 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-pro424 (accessed [today's date]).

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