Is ALK p.Arg918= (c.2754A>G) pathogenic?

ALK p.Arg918= (c.2754A>G) is classified Likely benign in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). Low-frequency (popmax 3.69%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Arg918= (c.2754A>G)?

ALK p.Arg918= (c.2754A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Arg918= (c.2754A>G) in the general population?

ALK p.Arg918= (c.2754A>G) is low-frequency (popmax 3.69%, sas) (gnomAD).

ALK p.Arg918=

c.2754A>G · VCV3284442

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 3.69%, sas)

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 7.8	GERP 0.93, phastCons 1
Overall
CADD	14.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.69% South Asian · 1,168/31,650 alleles

Filtering AF 3.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.44%

Overall 1.73% 6,093/352,678 alleles · low-frequency exomes 5,985/344,458 · genomes 108/8,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	3.69%	27
African / African-American	2.56%	39
Remaining individualsnot grpmax-eligible	2.3%	43
Admixed American	2.12%	47
East Asian	2.07%	48
Ashkenazi Jewishnot grpmax-eligible	1.54%	65
European (non-Finnish)	1.44%	69
Finnishnot grpmax-eligible	1.02%	98
Middle Eastern	0.996%	100

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.Arg918=
Coding: c.2754A>G
MANE Select: NM_004304
Type: single nucleotide variant
Location: chr2:29228945 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 918: an α-helix

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

Similar variants

ALK p.Arg918Ser Uncertain significance ★★ ⚠ same residue
ALK p.Arg918Thr Uncertain significance ★★ ⚠ same residue
ALK p.Arg918Gly Likely benign ★ same residue
ALK p.Arg918del 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-arg918 (accessed [today's date]).

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