Is INS p.Phe48Ser (c.143T>C) pathogenic?

INS p.Phe48Ser (c.143T>C) is classified Pathogenic in INS (ClinVar, No assertion criteria, 1 submitter; last evaluated 1993-01-15). AlphaMissense: likely pathogenic (0.9756); Absent from gnomAD v4.1; Associated with hyperproinsulinemia.

What condition is associated with INS p.Phe48Ser (c.143T>C)?

INS p.Phe48Ser (c.143T>C) is associated with hyperproinsulinemia (ClinVar).

How common is INS p.Phe48Ser (c.143T>C) in the general population?

INS p.Phe48Ser (c.143T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INS p.Phe48Ser (c.143T>C)?

AlphaMissense predicts likely pathogenic (score 0.9756) — an in-silico prediction, not a clinical call.

INS p.Phe48Ser

c.143T>C · rs80356668 · VCV13378

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9756 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperproinsulinemia

Computational evidence

Protein change
AlphaMissense	0.9756	likely pathogenic ✓ concordant with ClinVar · top 7% in INS
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 0.26, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,060 bp · p 0.36 · regional, not allelic
Overall
CADD	27.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: INS
Protein: p.Phe48Ser
Coding: c.143T>C
MANE Select: NM_000207
dbSNP: rs80356668
Type: single nucleotide variant
Location: chr11:2160829 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 48: a UniProt-annotated variant site (in pndm4); a UniProt-annotated variant site (in hpri; los-angeles); a β-strand

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

Disease context

hyperproinsulinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INS c.-152C>A Pathogenic/Likely pathogenic ★★ same condition
INS c.-152C>G Pathogenic ★★ same condition
INS p.Arg89His Pathogenic/Likely pathogenic ★★ same condition
INS p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
INS c.187+3G>A Uncertain significance ★★ same condition
INS c.-152C>T Uncertain significance ★★ same condition
INS p.Ala12Val Uncertain significance ★★ ⚠ same condition
INS p.Gly71Val 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/ins-p-phe48ser (accessed [today's date]).

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