Is ATM p.Ser2134Pro (c.6400T>C) pathogenic?

ATM p.Ser2134Pro (c.6400T>C) is classified Uncertain significance in ATM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.8579); Ultra-rare (popmax 0.0231%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Ser2134Pro (c.6400T>C)?

ATM p.Ser2134Pro (c.6400T>C) is associated with hereditary neoplastic syndrome, ataxia telangiectasia, hereditary breast carcinoma (ClinVar).

How common is ATM p.Ser2134Pro (c.6400T>C) in the general population?

ATM p.Ser2134Pro (c.6400T>C) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

What do computational predictors say about ATM p.Ser2134Pro (c.6400T>C)?

AlphaMissense predicts likely pathogenic (score 0.8579) — an in-silico prediction, not a clinical call.

ATM p.Ser2134Pro

c.6400T>C · rs758446561 · VCV490652

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8579 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8579	likely pathogenic · top 10% in ATM
REVEL	0.553	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.19, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 60 kb · p 6.4e-07 · regional, not allelic
Overall
CADD	21.3	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 0.0231% South Asian · 21/91,038 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00136% 22/1,612,492 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,335
Remaining individualsnot grpmax-eligible	0.0016%	62,416

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.Ser2134Pro
Coding: c.6400T>C
MANE Select: NM_000051
dbSNP: rs758446561
Type: single nucleotide variant
Location: chr11:108320006 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2134: a UniProt-annotated variant site (in at; uncertain significance; reduces protein abundance); a UniProt-annotated variant site (in at); the fat domain; a UniProt-annotated variant site (in at; uncertain significance); an α-helix; 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.Ser2134Cys Uncertain significance ★★ ⚠ same residue
ATM p.Ser2134Phe Uncertain significance ★ same residue
ATM p.Ser2134Tyr Uncertain significance ★ same residue
ATM p.Ser2134_Leu2135insTer Pathogenic ★★ same residue
ATM p.Ser2134fs 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

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-ser2134pro (accessed [today's date]).

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