Is CST5 p.Val126Phe (c.376G>T) pathogenic?

CST5 p.Val126Phe (c.376G>T) is classified Uncertain significance in CST5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-06). AlphaMissense: likely benign (0.3346); Ultra-rare (popmax 0.012%, afr).

How common is CST5 p.Val126Phe (c.376G>T) in the general population?

CST5 p.Val126Phe (c.376G>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CST5 p.Val126Phe (c.376G>T)?

AlphaMissense predicts likely benign (score 0.3346) — an in-silico prediction, not a clinical call.

CST5 p.Val126Phe

c.376G>T · VCV3497974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3346 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3346	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -2.5
Regional constraint	o/e 1.25	unconstrained · MANE · 3,485 bp · p 0.00076 · regional, not allelic
Overall
CADD	17.18	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 0.012% African / African-American · 9/75,034 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000682% 11/1,613,792 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,337
European (non-Finnish)	0.00017%	589,852

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: CST5
Protein: p.Val126Phe
Coding: c.376G>T
MANE Select: NM_001900
Type: single nucleotide variant
Location: chr20:23876241 (GRCh38)
Gene constraint: LOEUF 1.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.46 · 2 PDB
Residue 126: a β-strand; a disulfide bond

Full CST5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST5 p.Ala23Thr Uncertain significance ★ ⚠ same type
CST5 p.Ala31Thr Uncertain significance ★ ⚠ same type
CST5 p.Ala36Val Uncertain significance ★ ⚠ same type
CST5 p.Ala51Val Uncertain significance ★ ⚠ same type
CST5 p.Arg140Trp Uncertain significance ★ ⚠ same type
CST5 p.Asn101Ser Uncertain significance ★ ⚠ same type
CST5 p.Asn83His Uncertain significance ★ ⚠ same type
CST5 p.Asp41Gly 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/cst5-p-val126phe (accessed [today's date]).

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