Is IGFALS p.Arg595Trp (c.1783C>T) pathogenic?

IGFALS p.Arg595Trp (c.1783C>T) is classified Uncertain significance in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-15). AlphaMissense: likely pathogenic (0.7446); Ultra-rare (popmax 0.0162%, eas).

How common is IGFALS p.Arg595Trp (c.1783C>T) in the general population?

IGFALS p.Arg595Trp (c.1783C>T) is ultra-rare (popmax 0.0162%, eas) (gnomAD).

What do computational predictors say about IGFALS p.Arg595Trp (c.1783C>T)?

AlphaMissense predicts likely pathogenic (score 0.7446) — an in-silico prediction, not a clinical call.

IGFALS p.Arg595Trp

c.1783C>T · rs776312123 · VCV3069037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7446 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0162%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7446	likely pathogenic
REVEL	0.391	indeterminate
SaProt	LLR -12.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP -0.41, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0162% East Asian · 7/43,118 alleles

Filtering AF 0.00752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00531%

Overall 0.00404% 64/1,582,922 alleles · ultra-rare exomes 61/1,430,592 · genomes 3/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0162%	6,160
Admixed American	0.00546%	18,313
European (non-Finnish)	0.00429%	23,315
South Asian	0.00346%	28,941
Remaining individualsnot grpmax-eligible	0.00163%	61,378

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.Arg595Trp
Coding: c.1783C>T
MANE Select: NM_004970
dbSNP: rs776312123
Type: single nucleotide variant
Location: chr16:1790635 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 595: the lrrct domain

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

Similar variants

IGFALS p.Asn276Ser Likely pathogenic ★★ same type
IGFALS p.Ala147Thr Uncertain significance ★★ ⚠ same type
IGFALS p.Ala229Thr Uncertain significance ★★ ⚠ same type
IGFALS p.Ala258Val Uncertain significance ★★ ⚠ same type
IGFALS p.Ala551Thr Uncertain significance ★★ ⚠ same type
IGFALS p.Arg157His Uncertain significance ★★ ⚠ same type
IGFALS p.Arg306Gln Uncertain significance ★★ ⚠ same type
IGFALS p.Arg308His Uncertain significance ★★ ⚠ same type

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-arg595trp (accessed [today's date]).

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