Is CLK4 p.Val73Ile (c.217G>A) pathogenic?

CLK4 p.Val73Ile (c.217G>A) is classified Likely benign in CLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-30). AlphaMissense: likely benign (0.0742); Ultra-rare (popmax 0.0154%, sas).

How common is CLK4 p.Val73Ile (c.217G>A) in the general population?

CLK4 p.Val73Ile (c.217G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about CLK4 p.Val73Ile (c.217G>A)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

CLK4 p.Val73Ile

c.217G>A · rs140703998 · VCV2211987

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.69	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 -1.4	GERP -4.7
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	6.363	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 14/91,084 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00279% 45/1,613,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
Admixed American	0.00667%	14,995
European (non-Finnish)	0.0022%	45,380
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: CLK4
Protein: p.Val73Ile
Coding: c.217G>A
MANE Select: NM_020666
dbSNP: rs140703998
Type: single nucleotide variant
Location: chr5:178618723 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.48 · 1 PDB

Full CLK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLK4 p.Ala469Gly Uncertain significance ★ same type
CLK4 p.Arg110Gly Uncertain significance ★ ⚠ same type
CLK4 p.Arg117His Uncertain significance ★ ⚠ same type
CLK4 p.Arg156Lys Uncertain significance ★ ⚠ same type
CLK4 p.Arg198Cys Uncertain significance ★ ⚠ same type
CLK4 p.Arg202Cys Uncertain significance ★ ⚠ same type
CLK4 p.Arg221Gln Uncertain significance ★ ⚠ same type
CLK4 p.Arg24His 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/clk4-p-val73ile (accessed [today's date]).

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