Is IPP p.Val581Ile (c.1741G>A) pathogenic?

IPP p.Val581Ile (c.1741G>A) is classified Uncertain significance in IPP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.0729); Very rare (popmax 0.00667%, amr).

How common is IPP p.Val581Ile (c.1741G>A) in the general population?

IPP p.Val581Ile (c.1741G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about IPP p.Val581Ile (c.1741G>A)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

IPP p.Val581Ile

c.1741G>A · rs754518855 · VCV3110371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -5.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.077	GERP -1, phastCons 0.21
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.041 · regional, not allelic
Overall
CADD	17.27	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 0.00667% Admixed American · 4/59,994 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00167% 27/1,614,046 alleles · very rare exomes 26/1,461,858 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
East Asian	0.00223%	44,900
European (non-Finnish)	0.00169%	59,001
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	64,044

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: IPP
Protein: p.Val581Ile
Coding: c.1741G>A
MANE Select: NM_005897
dbSNP: rs754518855
Type: single nucleotide variant
Location: chr1:45699980 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.12

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

Similar variants

IPP p.Ala203Gly Uncertain significance ★ ⚠ same type
IPP p.Ala204Val Uncertain significance ★ same type
IPP p.Ala374Val Uncertain significance ★ ⚠ same type
IPP p.Ala476Val Uncertain significance ★ ⚠ same type
IPP p.Ala524Val Uncertain significance ★ same type
IPP p.Ala57Ser Uncertain significance ★ ⚠ same type
IPP p.Arg283Trp Uncertain significance ★ ⚠ same type
IPP p.Arg298Gln 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/ipp-p-val581ile (accessed [today's date]).

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