Is ALK p.Pro43Ser (c.127C>T) pathogenic?

ALK p.Pro43Ser (c.127C>T) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.1147); Ultra-rare (popmax 0.0166%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Pro43Ser (c.127C>T)?

ALK p.Pro43Ser (c.127C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Pro43Ser (c.127C>T) in the general population?

ALK p.Pro43Ser (c.127C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ALK p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely benign (score 0.1147) — an in-silico prediction, not a clinical call.

ALK p.Pro43Ser

c.127C>T · VCV4040499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1147 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1147	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	24.5	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,040 alleles

Overall 0.000124% 2/1,609,514 alleles · ultra-rare exomes 2/1,457,246 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,040
South Asian	0.0011%	90,900

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.Pro43Ser
Coding: c.127C>T
MANE Select: NM_004304
Type: single nucleotide variant
Location: chr2:29920533 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB

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.Pro43Arg Uncertain significance ★★ ⚠ same residue
ALK p.Pro43Leu Uncertain significance ★★ ⚠ same residue
ALK p.Pro43Thr Uncertain significance ★ ⚠ same residue
ALK p.Pro43= Likely 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

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-pro43ser (accessed [today's date]).

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