Is KIF12 p.Pro554Ser (c.1660C>T) pathogenic?

KIF12 p.Pro554Ser (c.1660C>T) is classified Uncertain significance in KIF12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-17). AlphaMissense: likely benign (0.076); Very rare (popmax 0.00187%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KIF12 p.Pro554Ser (c.1660C>T)?

KIF12 p.Pro554Ser (c.1660C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KIF12 p.Pro554Ser (c.1660C>T) in the general population?

KIF12 p.Pro554Ser (c.1660C>T) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about KIF12 p.Pro554Ser (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

KIF12 p.Pro554Ser

c.1660C>T · rs780468289 · VCV2486787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.74	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 1.6	GERP 0.99, phastCons 0.93
Regional constraint	o/e 0.95	unconstrained · MANE · 7,412 bp · p 0.12 · regional, not allelic
Overall
CADD	20.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P549S vs ClinVar P554S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% European (non-Finnish) · 22/1,178,424 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,607,844 alleles · very rare exomes 22/1,455,750 · genomes 1/152,094 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00187%	53,565
Remaining individualsnot grpmax-eligible	0.00161%	62,252

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: KIF12
Protein: p.Pro554Ser
Coding: c.1660C>T
MANE Select: NM_001388308
dbSNP: rs780468289
Type: single nucleotide variant
Location: chr9:114092579 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.01
Residue 549 UniProt numbering: a UniProt-annotated variant site (in pfic8); a UniProt-annotated variant site (found in a patient with liver cirrhosis; likely pathogenic; the orthologous mutation in a knockin mouse model results in features of liver steatosis with elevated liver triacylglycerol levels); the 'disordered' region

Full KIF12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KIF12 p.Ala417Thr Uncertain significance ★★ ⚠ same condition
KIF12 p.Arg333His Uncertain significance ★★ ⚠ same condition
KIF12 p.Arg468His Uncertain significance ★★ ⚠ same condition
KIF12 p.Gly609Arg Uncertain significance ★★ ⚠ same condition
KIF12 p.Leu356Val Uncertain significance ★★ ⚠ same condition
KIF12 p.Trp521Gly Uncertain significance ★★ ⚠ same condition
KIF12 p.Ala144Ser Uncertain significance ★ ⚠ same condition
KIF12 p.Ala144Thr 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/kif12-p-pro554ser (accessed [today's date]).

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