Is SI p.Ser60Pro (c.178T>C) pathogenic?

SI p.Ser60Pro (c.178T>C) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-13). AlphaMissense: likely benign (0.0719); Very rare (popmax 0.0034%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SI p.Ser60Pro (c.178T>C)?

SI p.Ser60Pro (c.178T>C) is associated with Inborn genetic diseases, congenital sucrase-isomaltase deficiency (ClinVar).

How common is SI p.Ser60Pro (c.178T>C) in the general population?

SI p.Ser60Pro (c.178T>C) is very rare (popmax 0.0034%, nfe) (gnomAD).

What do computational predictors say about SI p.Ser60Pro (c.178T>C)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

SI p.Ser60Pro

c.178T>C · rs755487744 · VCV1360738

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0034%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -5.88	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 -0.28	GERP -3.2
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	1.95	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 0.0034% European (non-Finnish) · 40/1,177,488 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00267% 43/1,610,392 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0034%	29,437
Remaining individualsnot grpmax-eligible	0.00321%	31,156
African / African-American	0.00134%	74,792

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.Ser60Pro
Coding: c.178T>C
MANE Select: NM_001041
dbSNP: rs755487744
Type: single nucleotide variant
Location: chr3:165074608 (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 60: the 'disordered' region

Full SI 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

Also linked: congenital sucrase-isomaltase deficiency

Similar variants

SI p.Ser60= Likely benign ★ 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-ser60pro (accessed [today's date]).

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