Is INVS p.Ala58Pro (c.172G>C) pathogenic?

INVS p.Ala58Pro (c.172G>C) is classified Uncertain significance in INVS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-10). AlphaMissense: likely pathogenic (0.9926); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with INVS p.Ala58Pro (c.172G>C)?

INVS p.Ala58Pro (c.172G>C) is associated with Inborn genetic diseases (ClinVar).

How common is INVS p.Ala58Pro (c.172G>C) in the general population?

INVS p.Ala58Pro (c.172G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about INVS p.Ala58Pro (c.172G>C)?

AlphaMissense predicts likely pathogenic (score 0.9926) — an in-silico prediction, not a clinical call.

INVS p.Ala58Pro

c.172G>C · VCV4276075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9926	likely pathogenic · top 9% in INVS
REVEL	0.538	indeterminate
SaProt	LLR -12.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 142 kb · p 0.1 · regional, not allelic
Overall
CADD	31.0	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,970 alleles · very rare exomes 1/1,461,778 · genomes 1/152,192 · joint denominator

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: INVS
Protein: p.Ala58Pro
Coding: c.172G>C
MANE Select: NM_014425
Type: single nucleotide variant
Location: chr9:100126448 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76

Full INVS 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

INVS p.Ala558Thr Uncertain significance ★★ ⚠ same condition
INVS p.Ala814Val Uncertain significance ★★ ⚠ same condition
INVS p.Ala926Thr Uncertain significance ★★ ⚠ same condition
INVS p.Arg123Gln Uncertain significance ★★ ⚠ same condition
INVS p.Arg339Ser Uncertain significance ★★ ⚠ same condition
INVS p.Arg536Cys Uncertain significance ★★ ⚠ same condition
INVS p.Arg536His Uncertain significance ★★ ⚠ same condition
INVS p.Arg576Gln 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/invs-p-ala58pro (accessed [today's date]).

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