Is PARD3 p.Arg349His (c.1046G>A) pathogenic?

PARD3 p.Arg349His (c.1046G>A) is classified Uncertain significance in PARD3 (ClinVar, Single submitter, 2 submitters; last evaluated 2017-10-01). AlphaMissense: likely benign (0.1538); Rare (popmax 0.365%, eas); Associated with neural tube defect.

What condition is associated with PARD3 p.Arg349His (c.1046G>A)?

PARD3 p.Arg349His (c.1046G>A) is associated with neural tube defect (ClinVar).

How common is PARD3 p.Arg349His (c.1046G>A) in the general population?

PARD3 p.Arg349His (c.1046G>A) is rare (popmax 0.365%, eas) (gnomAD).

What do computational predictors say about PARD3 p.Arg349His (c.1046G>A)?

AlphaMissense predicts likely benign (score 0.1538) — an in-silico prediction, not a clinical call.

PARD3 p.Arg349His

c.1046G>A · rs199923448 · VCV254188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1538 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.365%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neural tube defect

Computational evidence

Protein change
AlphaMissense	0.1538	likely benign
REVEL	0.541	indeterminate
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 406 kb · p 0.14 · regional, not allelic
Overall
CADD	28.1	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 0.365% East Asian · 164/44,872 alleles

Filtering AF 0.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.302%

Overall 0.0119% 192/1,613,990 alleles · rare exomes 181/1,461,816 · genomes 11/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.365%	274
Remaining individualsnot grpmax-eligible	0.0064%	15,626
African / African-American	0.004%	24,998
Admixed American	0.00333%	30,002
European (non-Finnish)	0.00153%	65,555
South Asian	0.0011%	91,046

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: PARD3
Protein: p.Arg349His
Coding: c.1046G>A
MANE Select: NM_001184785
dbSNP: rs199923448
Type: single nucleotide variant
Location: chr10:34382893 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.37 · 1 PDB
Residue 349: the pdz 1 domain; a UniProt-annotated variant site (in ntd; uncertain significance)

Full PARD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neural tube defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PARD3 p.Asp780Gly Pathogenic ⚠ same condition
PARD3 p.Pro910Gln Pathogenic ⚠ same condition
PARD3 c.2560+10A>G Benign ★★ same type
PARD3 p.Ala934Val Benign ★★ same type
PARD3 p.Glu107Asp Benign ★★ same type
PARD3 p.Glu1252= Benign/Likely benign ★★ same type
PARD3 p.Ser798Asn Benign ★★ same type
ASIP p.Ser72Pro 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/pard3-p-arg349his (accessed [today's date]).

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