Is ALK p.Ser277Phe (c.830C>T) pathogenic?

ALK p.Ser277Phe (c.830C>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.2208); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ser277Phe (c.830C>T)?

ALK p.Ser277Phe (c.830C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ser277Phe (c.830C>T) in the general population?

ALK p.Ser277Phe (c.830C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ALK p.Ser277Phe (c.830C>T)?

AlphaMissense predicts likely benign (score 0.2208) — an in-silico prediction, not a clinical call.

ALK p.Ser277Phe

c.830C>T · rs1486167712 · VCV567231

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2208	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -7.78	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 9.9	GERP 2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	23.8	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 0.00267% African / African-American · 2/74,894 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,613,894 alleles · very rare exomes 17/1,461,806 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,447
European (non-Finnish)	0.00144%	69,410

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.Ser277Phe
Coding: c.830C>T
MANE Select: NM_004304
dbSNP: rs1486167712
Type: single nucleotide variant
Location: chr2:29694972 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 277: the mam 1 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.Ser277= Likely benign ★★ same residue
ALK p.Ser277Ala Uncertain significance ★ ⚠ same residue
ALK p.Ser277Cys Uncertain significance ★ ⚠ same residue
ALK p.Ser277Tyr Uncertain significance ★ ⚠ same residue
ALK p.Ser277Pro 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

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-ser277phe (accessed [today's date]).

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