Is CASP14 p.Pro78Thr (c.232C>A) pathogenic?

CASP14 p.Pro78Thr (c.232C>A) is classified Uncertain significance in CASP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.0793); Ultra-rare (popmax 0.0151%, nfe).

How common is CASP14 p.Pro78Thr (c.232C>A) in the general population?

CASP14 p.Pro78Thr (c.232C>A) is ultra-rare (popmax 0.0151%, nfe) (gnomAD).

What do computational predictors say about CASP14 p.Pro78Thr (c.232C>A)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

CASP14 p.Pro78Thr

c.232C>A · VCV3995604

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0151%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.01	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 2.1	GERP -1.4, phastCons 0.55
Regional constraint	o/e 1.03	unconstrained · MANE · 3,834 bp · p 0.56 · regional, not allelic
Overall
CADD	12.69	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 0.0151% European (non-Finnish) · 178/1,180,002 alleles

Filtering AF 0.0132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.0112% 181/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0151%	6,629
African / African-American	0.00267%	37,445
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro78Thr
Coding: c.232C>A
MANE Select: NM_012114
Type: single nucleotide variant
Location: chr19:15053787 (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

Similar variants

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CASP14 c.404-151A>C Benign ★★ same type
CASP14 c.404-271T>C Benign ★★ same type
CASP14 c.520+77T>C Benign ★★ same type
CASP14 c.625-34G>T Benign ★★ same type
CASP14 c.-46-101T>A Benign ★★ same type
CASP14 c.-46-259A>G Benign ★★ 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/casp14-p-pro78thr (accessed [today's date]).

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