Is PYCR2 p.Val65Ile (c.193G>A) pathogenic?

PYCR2 p.Val65Ile (c.193G>A) is classified Uncertain significance in PYCR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-07). AlphaMissense: likely benign (0.0769); Ultra-rare (popmax 0.066%, mid); Associated with Inborn genetic diseases.

What condition is associated with PYCR2 p.Val65Ile (c.193G>A)?

PYCR2 p.Val65Ile (c.193G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PYCR2 p.Val65Ile (c.193G>A) in the general population?

PYCR2 p.Val65Ile (c.193G>A) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about PYCR2 p.Val65Ile (c.193G>A)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

PYCR2 p.Val65Ile

c.193G>A · rs150712428 · VCV1345482

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -5.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.8, phastCons 0.98
Regional constraint	o/e 0.90	unconstrained · MANE · 3,652 bp · p 0.034 · regional, not allelic
Overall
CADD	21.8	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0122% 197/1,614,192 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.015%	6,671
European (non-Finnish)	0.0144%	6,941
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
East Asian	0.00223%	44,894

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: PYCR2
Protein: p.Val65Ile
Coding: c.193G>A
MANE Select: NM_013328
dbSNP: rs150712428
Type: single nucleotide variant
Location: chr1:225922329 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.60 · 2 PDB
Residue 65: a β-strand

Full PYCR2 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

PYCR2 p.Arg200Cys Uncertain significance ★★ ⚠ same condition
PYCR2 p.Ile82Thr Uncertain significance ★★ ⚠ same condition
PYCR2 p.Thr139Ser Uncertain significance ★★ ⚠ same condition
PYCR2 p.Val143Met Uncertain significance ★★ ⚠ same condition
PYCR2 p.Val92Met Uncertain significance ★★ ⚠ same condition
PYCR2 p.Ala181Ser Likely pathogenic ★ ⚠ same condition
PYCR2 p.Ala22Ser Uncertain significance ★ ⚠ same condition
PYCR2 p.Ala281Thr 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/pycr2-p-val65ile (accessed [today's date]).

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