Is IGFALS p.Ala40Val (c.119C>T) pathogenic?

IGFALS p.Ala40Val (c.119C>T) is classified Uncertain significance in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0759); Rare (popmax 0.147%, afr); Associated with Inborn genetic diseases.

What condition is associated with IGFALS p.Ala40Val (c.119C>T)?

IGFALS p.Ala40Val (c.119C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IGFALS p.Ala40Val (c.119C>T) in the general population?

IGFALS p.Ala40Val (c.119C>T) is rare (popmax 0.147%, afr) (gnomAD).

What do computational predictors say about IGFALS p.Ala40Val (c.119C>T)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

IGFALS p.Ala40Val

c.119C>T · rs146602902 · VCV3108586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -7.89	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 -1.9	GERP -4.9
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	1.538	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.147% African / African-American · 110/75,024 alleles

Filtering AF 0.124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.116%

Overall 0.00782% 125/1,598,656 alleles · rare exomes 54/1,446,310 · genomes 71/152,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.147%	682
Remaining individualsnot grpmax-eligible	0.0113%	8,888
Admixed American	0.00667%	14,986
East Asian	0.00223%	44,852
European (non-Finnish)	0.000254%	393,063

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.Ala40Val
Coding: c.119C>T
MANE Select: NM_004970
dbSNP: rs146602902
Type: single nucleotide variant
Location: chr16:1792299 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 40: the lrrnt domain

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-ala40val (accessed [today's date]).

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