Is CAST p.Ser231Leu (c.692C>T) pathogenic?

CAST p.Ser231Leu (c.692C>T) is classified Uncertain significance in CAST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-21). AlphaMissense: likely benign (0.0824); Rare (popmax 0.148%, mid); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Ser231Leu (c.692C>T)?

CAST p.Ser231Leu (c.692C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Ser231Leu (c.692C>T) in the general population?

CAST p.Ser231Leu (c.692C>T) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about CAST p.Ser231Leu (c.692C>T)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

CAST p.Ser231Leu

c.692C>T · rs766024591 · VCV2174011

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor loss · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 1.4, phastCons 0.79
Overall
CADD	24.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S148L vs ClinVar S231L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.148% Middle Eastern · 9/6,064 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00473% 76/1,605,910 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	674
South Asian	0.00661%	15,131
Finnishnot grpmax-eligible	0.00627%	15,937
European (non-Finnish)	0.00443%	22,566
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,548
Remaining individualsnot grpmax-eligible	0.00322%	31,084
Admixed American	0.00167%	59,848
African / African-American	0.00134%	74,606

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: CAST
Protein: p.Ser231Leu
Coding: c.692C>T
dbSNP: rs766024591
Type: single nucleotide variant
Location: chr5:96736233 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 231: the 'disordered' region

Full CAST 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

PCSK1 p.Tyr231Cys Uncertain significance ★ ⚠ same residue
CAST p.Ser231= Benign ★ same residue
CAST p.Ala329Gly Uncertain significance ★★ ⚠ same condition
CAST p.Asp160Val Uncertain significance ★★ ⚠ same condition
CAST p.Gln731His Uncertain significance ★★ ⚠ same condition
CAST p.Glu296Gly Uncertain significance ★★ ⚠ same condition
CAST p.Ile274Val Uncertain significance ★★ ⚠ same condition
CAST p.Leu586Pro 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/cast-p-ser231leu (accessed [today's date]).

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