Is ATM p.Asp1226Val (c.3677A>T) pathogenic?

ATM p.Asp1226Val (c.3677A>T) is classified Uncertain significance in ATM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-12-08). AlphaMissense: likely benign (0.127); Very rare (popmax 8.8e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Asp1226Val (c.3677A>T)?

ATM p.Asp1226Val (c.3677A>T) is associated with hereditary neoplastic syndrome, ataxia telangiectasia (ClinVar).

How common is ATM p.Asp1226Val (c.3677A>T) in the general population?

ATM p.Asp1226Val (c.3677A>T) is very rare (popmax 8.8e-05%, nfe) (gnomAD).

What do computational predictors say about ATM p.Asp1226Val (c.3677A>T)?

AlphaMissense predicts likely benign (score 0.127) — an in-silico prediction, not a clinical call.

ATM p.Asp1226Val

c.3677A>T · rs1555092445 · VCV485176

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.8e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.127	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.75 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.8e-05% European (non-Finnish) · 1/1,136,088 alleles

Overall 7.08e-05% 1/1,412,778 alleles · very rare

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.Asp1226Val
Coding: c.3677A>T
MANE Select: NM_000051
dbSNP: rs1555092445
Type: single nucleotide variant
Location: chr11:108282810 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1226: a UniProt-annotated variant site (in at); a UniProt-annotated variant site (in at; uncertain significance); 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

Similar variants

ATM p.Asp1226His Uncertain significance ★★ ⚠ same residue
ATM p.Asp1226= Benign/Likely benign ★★ same residue
ATM p.Asp1226Asn Uncertain significance ★ ⚠ same residue
ATM p.Asp1226Gly Conflicting classifications of pathogenicity ★ ⚠ 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-asp1226val (accessed [today's date]).

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