Is CTSA p.Ser46Phe (c.137C>T) pathogenic?

CTSA p.Ser46Phe (c.137C>T) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-06). AlphaMissense: likely benign (0.15); Very rare (popmax 0.00602%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTSA p.Ser46Phe (c.137C>T)?

CTSA p.Ser46Phe (c.137C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CTSA p.Ser46Phe (c.137C>T) in the general population?

CTSA p.Ser46Phe (c.137C>T) is very rare (popmax 0.00602%, nfe) (gnomAD).

What do computational predictors say about CTSA p.Ser46Phe (c.137C>T)?

AlphaMissense predicts likely benign (score 0.15) — an in-silico prediction, not a clinical call.

CTSA p.Ser46Phe

c.137C>T · rs910439232 · VCV2265015

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.15 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00602%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.15	likely benign
REVEL	0.582	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.68, phastCons 0.15
Regional constraint	o/e 0.92	unconstrained · MANE · 1,710 bp · p 0.19 · regional, not allelic
Overall
CADD	22.4	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 0.00602% European (non-Finnish) · 71/1,180,042 alleles

Filtering AF 0.00486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00447%

Overall 0.00506% 74/1,461,086 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00602%	16,620
Remaining individualsnot grpmax-eligible	0.0032%	31,251
Admixed American	0.00167%	60,034

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: CTSA
Protein: p.Ser46Phe
Coding: c.137C>T
MANE Select: NM_000308
dbSNP: rs910439232
Type: single nucleotide variant
Location: chr20:45891705 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB

Full CTSA 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

CTSA c.-17G>A Uncertain significance ★★ same condition
CTSA c.-41C>T Uncertain significance ★★ same condition
CTSA c.-6G>A Uncertain significance ★★ same condition
CTSA p.Ala150Thr Uncertain significance ★★ ⚠ same condition
CTSA p.Arg372Cys Uncertain significance ★★ ⚠ same condition
CTSA p.Gly454Val Uncertain significance ★★ ⚠ same condition
CTSA p.Gly52Ser Uncertain significance ★★ ⚠ same condition
CTSA p.Pro329Thr 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/ctsa-p-ser46phe (accessed [today's date]).

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