Is CASP14 p.Asp154fs (c.462_463del) pathogenic?

CASP14 p.Asp154fs (c.462463del) is classified Conflicting classifications of pathogenicity in CASP14 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-05-24). Rare (popmax 0.288%, amr); Associated with ichthyosis, congenital, autosomal recessive 12.

What condition is associated with CASP14 p.Asp154fs (c.462_463del)?

CASP14 p.Asp154fs (c.462_463del) is associated with ichthyosis, congenital, autosomal recessive 12 (ClinVar).

How common is CASP14 p.Asp154fs (c.462_463del) in the general population?

CASP14 p.Asp154fs (c.462_463del) is rare (popmax 0.288%, amr) (gnomAD).

CASP14 p.Asp154fs

c.462_463del · rs769277893 · VCV375306

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.288%, amr)

Conditions

ichthyosis, congenital, autosomal recessive 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP 1.2, phastCons 0.003
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.288% Admixed American · 173/59,996 alleles

Filtering AF 0.253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.24%

Overall 0.0196% 316/1,614,050 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.288%	347
Ashkenazi Jewishnot grpmax-eligible	0.111%	897
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.00602%	16,620
African / African-American	0.004%	25,005

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: CASP14
Protein: p.Asp154fs
Coding: c.462_463del
MANE Select: NM_012114
dbSNP: rs769277893
Type: Deletion
Location: chr19:15055215 (GRCh38)
Gene constraint: LOEUF 1.217 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44

Full CASP14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ichthyosis, congenital, autosomal recessive 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASP14 p.Ala111Val Uncertain significance ★ ⚠ same condition
CASP14 p.Glu110Lys 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/casp14-p-asp154fs (accessed [today's date]).

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