Is IK p.Ser417Phe (c.1250C>T) pathogenic?

IK p.Ser417Phe (c.1250C>T) is classified Uncertain significance in IK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely benign (0.1788); Very rare (popmax 0.000597%, nfe).

How common is IK p.Ser417Phe (c.1250C>T) in the general population?

IK p.Ser417Phe (c.1250C>T) is very rare (popmax 0.000597%, nfe) (gnomAD).

What do computational predictors say about IK p.Ser417Phe (c.1250C>T)?

AlphaMissense predicts likely benign (score 0.1788) — an in-silico prediction, not a clinical call.

IK p.Ser417Phe

c.1250C>T · rs1468955115 · VCV3108990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1788 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000597%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1788	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 2,481 bp · p 0.012 · regional, not allelic
Overall
CADD	23.2	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 0.000597% European (non-Finnish) · 7/1,172,634 alleles

Filtering AF 0.000248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000438% 7/1,599,618 alleles · very rare exomes 7/1,447,318 · genomes 0/152,300 · joint denominator

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: IK
Protein: p.Ser417Phe
Coding: c.1250C>T
MANE Select: NM_006083
dbSNP: rs1468955115
Type: single nucleotide variant
Location: chr5:140659810 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.95 · 5 PDB
Residue 417: a modified residue (phosphoserine)

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

Similar variants

IK p.Ala14Asp Uncertain significance ★ ⚠ same type
IK p.Ala446Ser Uncertain significance ★ same type
IK p.Arg214Cys Uncertain significance ★ ⚠ same type
IK p.Arg214His Uncertain significance ★ ⚠ same type
IK p.Arg334Gln Uncertain significance ★ ⚠ same type
IK p.Arg342Gln Uncertain significance ★ ⚠ same type
IK p.Arg342Trp Uncertain significance ★ ⚠ same type
IK p.Arg344Gln 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/ik-p-ser417phe (accessed [today's date]).

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