Is CLNK p.Pro178Arg (c.533C>G) pathogenic?

CLNK p.Pro178Arg (c.533C>G) is classified Uncertain significance in CLNK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1217); Ultra-rare (popmax 0.0165%, mid).

How common is CLNK p.Pro178Arg (c.533C>G) in the general population?

CLNK p.Pro178Arg (c.533C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLNK p.Pro178Arg (c.533C>G)?

AlphaMissense predicts likely benign (score 0.1217) — an in-silico prediction, not a clinical call.

CLNK p.Pro178Arg

c.533C>G · VCV4654498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1217 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1217	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -0.98, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 177 kb · p 0.097 · regional, not allelic
Overall
CADD	19.5	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,613,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Admixed American	0.00333%	29,996
African / African-American	0.00133%	75,032

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.Pro178Arg
Coding: c.533C>G
MANE Select: NM_052964
Type: single nucleotide variant
Location: chr4:10540563 (GRCh38)
Gene constraint: LOEUF 1.308 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 56.93
Residue 178: the 'disordered' region; the 'mediates interaction with lat, grb2, and fgr; involved in translocation to the glycolipid-enriched microdomain and restoration of bcr-induced calcium response in blnk-deficient dt40 cells expressing lat' region

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-pro178arg (accessed [today's date]).

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