Is INTU p.Pro20Ala (c.58C>G) pathogenic?

INTU p.Pro20Ala (c.58C>G) is classified Uncertain significance in INTU (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-11). AlphaMissense: likely benign (0.0651); Very rare (popmax 0.00848%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTU p.Pro20Ala (c.58C>G)?

INTU p.Pro20Ala (c.58C>G) is associated with Inborn genetic diseases (ClinVar).

How common is INTU p.Pro20Ala (c.58C>G) in the general population?

INTU p.Pro20Ala (c.58C>G) is very rare (popmax 0.00848%, nfe) (gnomAD).

What do computational predictors say about INTU p.Pro20Ala (c.58C>G)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

INTU p.Pro20Ala

c.58C>G · rs747779931 · VCV2883944

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.82	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 -1.3	GERP -0.27
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.19 · regional, not allelic
Overall
CADD	7.8	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 0.00848% European (non-Finnish) · 100/1,179,840 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00663% 107/1,613,796 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00848%	11,798
African / African-American	0.004%	24,970
Admixed American	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0032%	31,234

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: INTU
Protein: p.Pro20Ala
Coding: c.58C>G
MANE Select: NM_015693
dbSNP: rs747779931
Type: single nucleotide variant
Location: chr4:127633092 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.35 · 4 PDB
Residue 20: the 'disordered' region

Full INTU 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

INTU p.Pro20Leu Uncertain significance ★★ ⚠ same residue
INTU p.Ala611Thr Uncertain significance ★★ ⚠ same condition
INTU p.Ala804Val Uncertain significance ★★ ⚠ same condition
INTU p.Arg119Thr Uncertain significance ★★ ⚠ same condition
INTU p.Arg127Cys Uncertain significance ★★ ⚠ same condition
INTU p.Arg510Trp Uncertain significance ★★ ⚠ same condition
INTU p.Arg665Cys Uncertain significance ★★ ⚠ same condition
INTU p.Arg705Cys 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/intu-p-pro20ala (accessed [today's date]).

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