Is IGFALS p.Pro498Ser (c.1492C>T) pathogenic?

IGFALS p.Pro498Ser (c.1492C>T) is classified Conflicting classifications of pathogenicity in IGFALS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-24). AlphaMissense: likely benign (0.094); Rare (popmax 0.502%, afr); Associated with Inborn genetic diseases.

What condition is associated with IGFALS p.Pro498Ser (c.1492C>T)?

IGFALS p.Pro498Ser (c.1492C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IGFALS p.Pro498Ser (c.1492C>T) in the general population?

IGFALS p.Pro498Ser (c.1492C>T) is rare (popmax 0.502%, afr) (gnomAD).

What do computational predictors say about IGFALS p.Pro498Ser (c.1492C>T)?

AlphaMissense predicts likely benign (score 0.094) — an in-silico prediction, not a clinical call.

IGFALS p.Pro498Ser

c.1492C>T · rs9282730 · VCV724110

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.094 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.502%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.094	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -7.64	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 1.2	GERP -4.7, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	2.668	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 0.502% African / African-American · 376/74,830 alleles

Filtering AF 0.461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.444%

Overall 0.03% 477/1,592,076 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.502%	199
Remaining individualsnot grpmax-eligible	0.0452%	2,212
Admixed American	0.0411%	2,434
European (non-Finnish)	0.00417%	23,997

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.Pro498Ser
Coding: c.1492C>T
MANE Select: NM_004970
dbSNP: rs9282730
Type: single nucleotide variant
Location: chr16:1790926 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 498: a UniProt-annotated variant site (in)

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.Pro498= Likely benign ★ same residue
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

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-pro498ser (accessed [today's date]).

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