Is ATM p.Ser440Pro (c.1318T>C) pathogenic?

ATM p.Ser440Pro (c.1318T>C) is classified Uncertain significance in ATM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-30). AlphaMissense: ambiguous (0.4956); Very rare (popmax 8.47e-05%, nfe); Associated with ataxia telangiectasia.

What condition is associated with ATM p.Ser440Pro (c.1318T>C)?

ATM p.Ser440Pro (c.1318T>C) is associated with ataxia telangiectasia, hereditary neoplastic syndrome (ClinVar).

How common is ATM p.Ser440Pro (c.1318T>C) in the general population?

ATM p.Ser440Pro (c.1318T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Ataxia-telangiectasia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ATM p.Ser440Pro (c.1318T>C)?

AlphaMissense predicts ambiguous (score 0.4956) — an in-silico prediction, not a clinical call.

ATM p.Ser440Pro

c.1318T>C · rs2135318467 · VCV2453990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

ataxia telangiectasia

Computational evidence

Protein change
AlphaMissense	0.4956	ambiguous
REVEL	0.017	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 0.18, phastCons 0.18
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.75 · regional, not allelic
Overall
CADD	15.89	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 8.47e-05% European (non-Finnish) · 1/1,179,954 alleles

Overall 6.2e-05% 1/1,613,826 alleles · very rare exomes 1/1,461,758 · genomes 0/152,068 · joint denominator

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.Ser440Pro
Coding: c.1318T>C
MANE Select: NM_000051
dbSNP: rs2135318467
Type: single nucleotide variant
Location: chr11:108250783 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 440: 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

ataxia telangiectasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Ataxia-telangiectasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-5 / 10 000 (Norway)

Similar variants

ATM p.Ser440Phe Uncertain significance ★★ ⚠ same residue
ATM p.Ser440= Likely benign ★ 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
ATM c.332-1G>A Pathogenic ★★★ same condition
ATM c.4909+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-ser440pro (accessed [today's date]).

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