Is CTSA p.Phe248Leu (c.744C>G) pathogenic?

CTSA p.Phe248Leu (c.744C>G) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-26). AlphaMissense: likely pathogenic (0.9835); Absent from gnomAD v4.1.

How common is CTSA p.Phe248Leu (c.744C>G) in the general population?

CTSA p.Phe248Leu (c.744C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSA p.Phe248Leu (c.744C>G)?

AlphaMissense predicts likely pathogenic (score 0.9835) — an in-silico prediction, not a clinical call.

CTSA p.Phe248Leu

c.744C>G · rs1568763858 · VCV1303536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9835 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9835	likely pathogenic · top 8% in CTSA
REVEL	0.553	indeterminate
SaProt	LLR -10.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSA
Protein: p.Phe248Leu
Coding: c.744C>G
MANE Select: NM_000308
dbSNP: rs1568763858
Type: single nucleotide variant
Location: chr20:45894039 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 248: a disulfide bond

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

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CTSA c.692+3A>G Pathogenic ★★ same type
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CTSA p.Arg375Ter Pathogenic/Likely pathogenic ★★ same type
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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/ctsa-p-phe248leu (accessed [today's date]).

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