Is CSTB p.Ala49Val (c.146C>T) pathogenic?

CSTB p.Ala49Val (c.146C>T) is classified Uncertain significance in CSTB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-27). AlphaMissense: ambiguous (0.5503); Very rare (popmax 0.0022%, sas).

How common is CSTB p.Ala49Val (c.146C>T) in the general population?

CSTB p.Ala49Val (c.146C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CSTB p.Ala49Val (c.146C>T)?

AlphaMissense predicts ambiguous (score 0.5503) — an in-silico prediction, not a clinical call.

CSTB p.Ala49Val

c.146C>T · rs754421704 · VCV205326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5503 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
AlphaMissense	0.5503	ambiguous
REVEL	0.551	indeterminate
SaProt	LLR -10.07	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.93, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,064 bp · p 0.83 · regional, not allelic
Overall
CADD	23.6	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 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00105% 17/1,613,934 alleles · very rare exomes 15/1,461,738 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,910
European (non-Finnish)	0.0011%	90,765

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: CSTB
Protein: p.Ala49Val
Coding: c.146C>T
MANE Select: NM_000100
dbSNP: rs754421704
Type: single nucleotide variant
Location: chr21:43774680 (GRCh38)
Gene constraint: LOEUF 1.681 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.81 · 3 PDB
Residue 49: a β-strand

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

Similar variants

CSTB p.Ala49Thr Uncertain significance ★★ same residue
CSTB p.Ala49Glu Uncertain significance ★ ⚠ same residue
CSTB p.Ala49= Likely benign ★ same residue
CSTB p.Ala49fs Pathogenic ★★ same residue
CSTB c.67-1G>C Pathogenic ★★ same type
CSTB p.Arg68Ter Pathogenic ★★ same type
CSTB p.Gln22Ter Pathogenic/Likely pathogenic ★★ same type
CSTB p.Gln46Ter Pathogenic/Likely pathogenic ★★ 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/cstb-p-ala49val (accessed [today's date]).

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