Is CTSS p.Ala243Thr (c.727G>A) pathogenic?

CTSS p.Ala243Thr (c.727G>A) is classified Uncertain significance in CTSS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: likely benign (0.3227); Ultra-rare (popmax 0.0117%, amr).

How common is CTSS p.Ala243Thr (c.727G>A) in the general population?

CTSS p.Ala243Thr (c.727G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CTSS p.Ala243Thr (c.727G>A)?

AlphaMissense predicts likely benign (score 0.3227) — an in-silico prediction, not a clinical call.

CTSS p.Ala243Thr

c.727G>A · rs748861303 · VCV2225121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3227 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3227	likely benign
REVEL	0.73	pathogenic-leaning
SaProt	LLR -10.99	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 32 kb · p 1.1e-13 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,008 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000479% 7/1,461,734 alleles · ultra-rare

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: CTSS
Protein: p.Ala243Thr
Coding: c.727G>A
MANE Select: NM_004079
dbSNP: rs748861303
Type: single nucleotide variant
Location: chr1:150750072 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 94.51 · 62 PDB
Residue 243: an α-helix

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

Similar variants

CTSS p.Val296= Benign ★★ same type
CTSS p.Asp120Ala Uncertain significance ★ ⚠ same type
CTSS p.Asp74Asn Uncertain significance ★ ⚠ same type
CTSS p.Gly176Val Uncertain significance ★ ⚠ same type
CTSS p.His27Gln Uncertain significance ★ ⚠ same type
CTSS p.Ile193Thr Uncertain significance ★ ⚠ same type
CTSS p.Lys178Asn Uncertain significance ★ ⚠ same type
CTSS p.Lys212Gln Uncertain significance ★ ⚠ 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/ctss-p-ala243thr (accessed [today's date]).

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