Is ALK p.Thr1012Met (c.3035C>T) pathogenic?

ALK p.Thr1012Met (c.3035C>T) is classified Benign/Likely benign in ALK (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0636); Low-frequency (popmax 1%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Thr1012Met (c.3035C>T)?

ALK p.Thr1012Met (c.3035C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Thr1012Met (c.3035C>T) in the general population?

ALK p.Thr1012Met (c.3035C>T) is low-frequency (popmax 1%, eas) (gnomAD).

What do computational predictors say about ALK p.Thr1012Met (c.3035C>T)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

ALK p.Thr1012Met

c.3035C>T · rs35073634 · VCV133465

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.331	indeterminate
SaProt	LLR -2.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 26 kb · p 0.039 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1% East Asian · 449/44,884 alleles

Filtering AF 0.924% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.894%

Overall 0.0457% 738/1,614,208 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1%	100
Ashkenazi Jewishnot grpmax-eligible	0.0912%	1,097
South Asian	0.0703%	1,423
Remaining individualsnot grpmax-eligible	0.0464%	2,156
European (non-Finnish)	0.0136%	7,375
African / African-American	0.00933%	10,723
Admixed American	0.00333%	30,015

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: ALK
Protein: p.Thr1012Met
Coding: c.3035C>T
MANE Select: NM_004304
dbSNP: rs35073634
Type: single nucleotide variant
Location: chr2:29226954 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1012: the 'egf-like' region; a β-strand; a disulfide bond; a UniProt-annotated variant site (in)

Full ALK 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: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Thr1012= Benign ★★ same residue
ALK p.Arg1275Gln Pathogenic ★★ same condition
ALK c.1154+5G>A Uncertain significance ★★ same condition
ALK c.1155-3C>T Uncertain significance ★★ same condition
ALK c.1282+3A>G Uncertain significance ★★ same condition
ALK c.1414+1G>A Uncertain significance ★★ same condition
ALK c.1414+3G>A Uncertain significance ★★ same condition
ALK c.1415-3T>C Uncertain significance ★★ 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/alk-p-thr1012met (accessed [today's date]).

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