Is SI p.Ser460Cys (c.1378A>T) pathogenic?

SI p.Ser460Cys (c.1378A>T) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1735); Ultra-rare (popmax 0.0261%, nfe); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Ser460Cys (c.1378A>T)?

SI p.Ser460Cys (c.1378A>T) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Ser460Cys (c.1378A>T) in the general population?

SI p.Ser460Cys (c.1378A>T) is ultra-rare (popmax 0.0261%, nfe) (gnomAD).

How is Congenital sucrase-isomaltase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SI p.Ser460Cys (c.1378A>T)?

AlphaMissense predicts likely benign (score 0.1735) — an in-silico prediction, not a clinical call.

SI p.Ser460Cys

c.1378A>T · rs141450837 · VCV1441406

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0261%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
AlphaMissense	0.1735	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.031	GERP -2.4
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	14.71	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 0.0261% European (non-Finnish) · 308/1,178,242 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0228%

Overall 0.0199% 320/1,611,452 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0261%	3,825
Remaining individualsnot grpmax-eligible	0.0144%	6,929
African / African-American	0.00401%	24,943

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: SI
Protein: p.Ser460Cys
Coding: c.1378A>T
MANE Select: NM_001041
dbSNP: rs141450837
Type: single nucleotide variant
Location: chr3:165058983 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB
Residue 460: the 'isomaltase' region; a β-strand

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

Disease context

congenital sucrase-isomaltase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital sucrase-isomaltase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SI p.Ser460= Uncertain significance ★ same residue
SI c.2426+1G>A Likely pathogenic ★★ same condition
SI c.2893-1G>A Likely pathogenic ★★ same condition
SI c.3099+1G>C Likely pathogenic ★★ same condition
SI c.3521-1G>T Likely pathogenic ★★ same condition
SI c.373+1G>A Likely pathogenic ★★ same condition
SI c.4575+2T>C Likely pathogenic ★★ same condition
SI c.4927-1G>A Likely pathogenic ★★ 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/si-p-ser460cys (accessed [today's date]).

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