Is IGFALS p.Arg509Ser (c.1525C>A) pathogenic?

IGFALS p.Arg509Ser (c.1525C>A) is classified Uncertain significance in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: ambiguous (0.3747); Very rare (popmax 0.00404%, afr); Associated with Inborn genetic diseases.

What condition is associated with IGFALS p.Arg509Ser (c.1525C>A)?

IGFALS p.Arg509Ser (c.1525C>A) is associated with Inborn genetic diseases (ClinVar).

How common is IGFALS p.Arg509Ser (c.1525C>A) in the general population?

IGFALS p.Arg509Ser (c.1525C>A) is very rare (popmax 0.00404%, afr) (gnomAD).

What do computational predictors say about IGFALS p.Arg509Ser (c.1525C>A)?

AlphaMissense predicts ambiguous (score 0.3747) — an in-silico prediction, not a clinical call.

IGFALS p.Arg509Ser

c.1525C>A · rs780196950 · VCV3108589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00404%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3747	ambiguous
REVEL	0.174	moderately benign-leaning
SaProt	LLR -8.84	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP -1.4, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	24.4	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 0.00404% African / African-American · 3/74,234 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000498%

Overall 0.000889% 14/1,574,664 alleles · very rare exomes 11/1,422,450 · genomes 3/152,214 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00404%	24,745
European (non-Finnish)	0.000944%	105,876

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.Arg509Ser
Coding: c.1525C>A
MANE Select: NM_004970
dbSNP: rs780196950
Type: single nucleotide variant
Location: chr16:1790893 (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.Arg509Cys Uncertain significance ★★ ⚠ same residue
IGFALS p.Arg509His 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

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-arg509ser (accessed [today's date]).

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