Is ATM p.Ile415Phe (c.1243A>T) pathogenic?

ATM p.Ile415Phe (c.1243A>T) is classified Conflicting classifications of pathogenicity in ATM (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-05-05). AlphaMissense: ambiguous (0.4479); Ultra-rare (popmax 0.0209%, mid); Associated with ataxia telangiectasia.

What condition is associated with ATM p.Ile415Phe (c.1243A>T)?

ATM p.Ile415Phe (c.1243A>T) is associated with ataxia telangiectasia (ClinVar).

How common is ATM p.Ile415Phe (c.1243A>T) in the general population?

ATM p.Ile415Phe (c.1243A>T) is ultra-rare (popmax 0.0209%, mid) (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.Ile415Phe (c.1243A>T)?

AlphaMissense predicts ambiguous (score 0.4479) — an in-silico prediction, not a clinical call.

ATM p.Ile415Phe

c.1243A>T · rs1591522756 · VCV802743

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4479 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, mid)

Conditions

ataxia telangiectasia

Computational evidence

Protein change
AlphaMissense	0.4479	ambiguous
REVEL	0.225	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.75 · regional, not allelic
Overall
CADD	24.9	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 0.0209% Middle Eastern · 1/4,788 alleles

Overall 0.000188% 3/1,591,772 alleles · ultra-rare exomes 3/1,446,140 · genomes 0/145,632 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0209%	4,788
Finnishnot grpmax-eligible	0.00187%	53,558
European (non-Finnish)	8.5e-05%	1,175,894

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.Ile415Phe
Coding: c.1243A>T
MANE Select: NM_000051
dbSNP: rs1591522756
Type: single nucleotide variant
Location: chr11:108250708 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 415: 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

For Ataxia-telangiectasia (Orphanet):

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

Similar variants

ATM p.Ile415Met Uncertain significance ★★ ⚠ same residue
ATM p.Ile415Asn Uncertain significance ★ same residue
ATM p.Ile415= Likely benign ★ same residue
ATM p.Ile415_Ala416insPhePhe 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

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-ile415phe (accessed [today's date]).

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