Is IGFALS p.Val89Ile (c.265G>A) pathogenic?

IGFALS p.Val89Ile (c.265G>A) is classified Likely benign in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0532); Very rare (popmax 0.0077%, sas); Associated with Inborn genetic diseases.

What condition is associated with IGFALS p.Val89Ile (c.265G>A)?

IGFALS p.Val89Ile (c.265G>A) is associated with Inborn genetic diseases (ClinVar).

How common is IGFALS p.Val89Ile (c.265G>A) in the general population?

IGFALS p.Val89Ile (c.265G>A) is very rare (popmax 0.0077%, sas) (gnomAD).

What do computational predictors say about IGFALS p.Val89Ile (c.265G>A)?

AlphaMissense predicts likely benign (score 0.0532) — an in-silico prediction, not a clinical call.

IGFALS p.Val89Ile

c.265G>A · VCV4622000

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0077%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0532	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.87	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 -1.4	GERP -5.1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	0.17	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

Grpmax group 0.0077% South Asian · 7/90,930 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00112% 18/1,611,392 alleles · very rare exomes 16/1,459,126 · genomes 2/152,266 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0077%	12,990
Admixed American	0.00501%	19,976
Remaining individualsnot grpmax-eligible	0.0016%	62,412
European (non-Finnish)	0.000593%	168,526

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.Val89Ile
Coding: c.265G>A
MANE Select: NM_004970
Type: single nucleotide variant
Location: chr16:1792153 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IGFALS p.Ala229Thr Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg157His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg308His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg332His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg375Trp Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg402His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg467Cys Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg509Cys 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-val89ile (accessed [today's date]).

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