Is SI p.Phe1401Leu (c.4203T>G) pathogenic?

SI p.Phe1401Leu (c.4203T>G) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.9968); Rare (popmax 0.108%, eas); Associated with congenital sucrase-isomaltase deficiency.

What condition is associated with SI p.Phe1401Leu (c.4203T>G)?

SI p.Phe1401Leu (c.4203T>G) is associated with congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Phe1401Leu (c.4203T>G) in the general population?

SI p.Phe1401Leu (c.4203T>G) is rare (popmax 0.108%, eas) (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.Phe1401Leu (c.4203T>G)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

SI p.Phe1401Leu

c.4203T>G · rs574552408 · VCV344015

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.108%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital sucrase-isomaltase deficiency

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 1% in SI
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -10.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.16, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.108% East Asian · 48/44,436 alleles

Filtering AF 0.0837% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.075%

Overall 0.00409% 65/1,588,332 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.108%	926
South Asian	0.0166%	6,033
Remaining individualsnot grpmax-eligible	0.00325%	30,783

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.Phe1401Leu
Coding: c.4203T>G
MANE Select: NM_001041
dbSNP: rs574552408
Type: single nucleotide variant
Location: chr3:165007975 (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 1401: the 'sucrase' region

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-phe1401leu (accessed [today's date]).

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