Is INS p.Phe49= (c.147C>T) pathogenic?

INS p.Phe49= (c.147C>T) is classified Conflicting classifications of pathogenicity in INS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-28). Ultra-rare (popmax 0.0481%, afr); Associated with hyperproinsulinemia.

What condition is associated with INS p.Phe49= (c.147C>T)?

INS p.Phe49= (c.147C>T) is associated with hyperproinsulinemia (ClinVar).

How common is INS p.Phe49= (c.147C>T) in the general population?

INS p.Phe49= (c.147C>T) is ultra-rare (popmax 0.0481%, afr) (gnomAD).

INS p.Phe49=

c.147C>T · rs148685531 · VCV1337436

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0481%, afr)

Conditions

hyperproinsulinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.1, phastCons 1
Overall
CADD	10.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0481% African / African-American · 36/74,912 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00254% 41/1,612,510 alleles · ultra-rare exomes 20/1,460,328 · genomes 21/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0481%	2,081
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0016%	62,448

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: INS
Protein: p.Phe49=
Coding: c.147C>T
MANE Select: NM_000207
dbSNP: rs148685531
Type: single nucleotide variant
Location: chr11:2160825 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 49: a UniProt-annotated variant site (in chicago); 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-IGF2 p.Phe49Leu Uncertain significance ★ ⚠ same residue
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

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-phe49 (accessed [today's date]).

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