Is IGFALS p.Ala92fs (c.269_272dup) pathogenic?

IGFALS p.Ala92fs (c.269272dup) is classified Likely pathogenic in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). Very rare (popmax 0.00636%, nfe); Associated with Monogenic short statue.

What condition is associated with IGFALS p.Ala92fs (c.269_272dup)?

IGFALS p.Ala92fs (c.269_272dup) is associated with Monogenic short statue (ClinVar).

How common is IGFALS p.Ala92fs (c.269_272dup) in the general population?

IGFALS p.Ala92fs (c.269_272dup) is very rare (popmax 0.00636%, nfe) (gnomAD).

IGFALS p.Ala92fs

c.269_272dup · VCV4281664

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Conditions

Monogenic short statue

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8.9	GERP -5.1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00636% European (non-Finnish) · 75/1,179,664 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00465% 75/1,611,400 alleles · very rare exomes 75/1,459,186 · genomes 0/152,214 · joint denominator

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: IGFALS
Protein: p.Ala92fs
Coding: c.269_272dup
MANE Select: NM_004970
Type: Duplication
Location: chr16:1792145 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB

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

Disease context

Monogenic short statue

Similar variants

IGFALS p.Glu35fs Pathogenic/Likely pathogenic ★★ same condition
IGFALS p.Pro555fs Likely pathogenic ★ same condition
IGFALS p.Glu495fs Conflicting classifications of pathogenicity ★ same condition
IGFALS p.Ser195_Arg197dup Conflicting classifications of pathogenicity ★ same condition
IGFALS p.Glu567fs Likely pathogenic ★ same condition
IGFALS p.Leu134Gln Pathogenic ★ same condition
IGFALS p.Phe602Cys Likely pathogenic ★ same condition
IGFALS p.Asn492Ser 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/igfals-p-ala92fs (accessed [today's date]).

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