Is ALK p.Asp1372His (c.4114G>C) pathogenic?

ALK p.Asp1372His (c.4114G>C) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-05). AlphaMissense: ambiguous (0.5363); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Asp1372His (c.4114G>C)?

ALK p.Asp1372His (c.4114G>C) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Asp1372His (c.4114G>C) in the general population?

ALK p.Asp1372His (c.4114G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ALK p.Asp1372His (c.4114G>C)?

AlphaMissense predicts ambiguous (score 0.5363) — an in-silico prediction, not a clinical call.

ALK p.Asp1372His

c.4114G>C · rs535864522 · VCV1737949

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5363 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5363	ambiguous
REVEL	0.593	indeterminate
SaProt	LLR -8.31	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 4,393 bp · p 0.054 · regional, not allelic
Overall
CADD	25.3	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 0.0011% South Asian · 1/91,086 alleles

Overall 0.000124% 2/1,614,188 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	8.47e-05%	1,179,997

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.Asp1372His
Coding: c.4114G>C
MANE Select: NM_004304
dbSNP: rs535864522
Type: single nucleotide variant
Location: chr2:29196820 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1372: an α-helix; the protein kinase domain

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.Asp1372= Likely benign ★★ same residue
ALK p.Asp1372Ala Uncertain significance ★ ⚠ same residue
ALK p.Asp1372Asn Uncertain significance ★ ⚠ same residue
ALK p.Asp1372Tyr Uncertain significance ★ ⚠ 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

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-asp1372his (accessed [today's date]).

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