Is CLNK p.Cys337Phe (c.1010G>T) pathogenic?

CLNK p.Cys337Phe (c.1010G>T) is classified Uncertain significance in CLNK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.5718); Very rare (popmax 0.00017%, nfe).

How common is CLNK p.Cys337Phe (c.1010G>T) in the general population?

CLNK p.Cys337Phe (c.1010G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CLNK p.Cys337Phe (c.1010G>T)?

AlphaMissense predicts likely pathogenic (score 0.5718) — an in-silico prediction, not a clinical call.

CLNK p.Cys337Phe

c.1010G>T · VCV4230078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5718	likely pathogenic
REVEL	0.485	indeterminate
SaProt	LLR -13.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.82, phastCons 0.99
Regional constraint	o/e 1.07	unconstrained · MANE · 177 kb · p 0.097 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,178,608 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,457,224 alleles · very rare

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: CLNK
Protein: p.Cys337Phe
Coding: c.1010G>T
MANE Select: NM_052964
Type: single nucleotide variant
Location: chr4:10501386 (GRCh38)
Gene constraint: LOEUF 1.308 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 56.93
Residue 337: the sh2 domain

Full CLNK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLNK p.Ile361= Benign ★★ same type
CLNK p.Pro31Leu Benign ★★ same type
CLNK p.Ala241Asp Uncertain significance ★ ⚠ same type
CLNK p.Arg184Lys Uncertain significance ★ ⚠ same type
CLNK p.Arg198Ser Uncertain significance ★ ⚠ same type
CLNK p.Arg257Thr Uncertain significance ★ ⚠ same type
CLNK p.Arg298Thr Uncertain significance ★ ⚠ same type
CLNK p.Arg32Gly Uncertain significance ★ ⚠ same type

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/clnk-p-cys337phe (accessed [today's date]).

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