Is SI p.Pro348Leu (c.1043C>T) pathogenic?

SI p.Pro348Leu (c.1043C>T) is classified Conflicting classifications of pathogenicity in SI (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.3889); Rare (popmax 0.252%, nfe); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Pro348Leu (c.1043C>T)?

SI p.Pro348Leu (c.1043C>T) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Pro348Leu (c.1043C>T) in the general population?

SI p.Pro348Leu (c.1043C>T) is rare (popmax 0.252%, 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.Pro348Leu (c.1043C>T)?

AlphaMissense predicts ambiguous (score 0.3889) — an in-silico prediction, not a clinical call.

SI p.Pro348Leu

c.1043C>T · rs77546399 · VCV344061

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3889 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.252%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
AlphaMissense	0.3889	ambiguous
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	29.4	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 0.252% European (non-Finnish) · 2,967/1,178,442 alleles

Filtering AF 0.244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.241%

Overall 0.196% 3,166/1,611,674 alleles · rare exomes 2,969/1,459,714 · genomes 197/151,960 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.252%	397
Remaining individualsnot grpmax-eligible	0.138%	725
Finnishnot grpmax-eligible	0.119%	840
African / African-American	0.0254%	3,942
Admixed American	0.0217%	4,604
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,845
South Asian	0.0022%	45,527

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.Pro348Leu
Coding: c.1043C>T
MANE Select: NM_001041
dbSNP: rs77546399
Type: single nucleotide variant
Location: chr3:165060005 (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 348: the 'isomaltase' region; an α-helix

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 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
SI c.5248-2A>C 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-pro348leu (accessed [today's date]).

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