Is ATM p.Phe627= (c.1881C>T) pathogenic?

ATM p.Phe627= (c.1881C>T) is classified Conflicting classifications of pathogenicity in ATM (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-02-10). Very rare (popmax 0.000255%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Phe627= (c.1881C>T)?

ATM p.Phe627= (c.1881C>T) is associated with hereditary neoplastic syndrome, ataxia telangiectasia, hereditary breast carcinoma (ClinVar).

How common is ATM p.Phe627= (c.1881C>T) in the general population?

ATM p.Phe627= (c.1881C>T) is very rare (popmax 0.000255%, nfe) (gnomAD).

ATM p.Phe627=

c.1881C>T · rs1555072574 · VCV453390

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1	GERP 0.018, phastCons 1
Overall
CADD	8.728	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,177,916 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,611,242 alleles · very rare exomes 4/1,459,082 · genomes 0/152,160 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,386
European (non-Finnish)grpmax	0.000255%	392,639

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe627=
Coding: c.1881C>T
MANE Select: NM_000051
dbSNP: rs1555072574
Type: single nucleotide variant
Location: chr11:108252895 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 627: 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

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.Phe627Cys Uncertain significance ★★ same residue
ATM p.Phe627Ser Uncertain significance ★★ same residue
ATM p.Phe627_Gln628delinsLeuLys Uncertain significance ★★ same residue
ATM p.Phe627fs 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
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-phe627 (accessed [today's date]).

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