Is PARD3 p.Arg1075Cys (c.3223C>T) pathogenic?

PARD3 p.Arg1075Cys (c.3223C>T) is classified Uncertain significance in PARD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: ambiguous (0.5523); Very rare (popmax 0.00446%, eas).

How common is PARD3 p.Arg1075Cys (c.3223C>T) in the general population?

PARD3 p.Arg1075Cys (c.3223C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PARD3 p.Arg1075Cys (c.3223C>T)?

AlphaMissense predicts ambiguous (score 0.5523) — an in-silico prediction, not a clinical call.

PARD3 p.Arg1075Cys

c.3223C>T · VCV3304310

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5523 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5523	ambiguous
REVEL	0.226	benign-leaning
SaProt	LLR -12.19	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 2.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 406 kb · p 0.14 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1078C vs ClinVar R1075C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,840 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00211% 34/1,613,632 alleles · very rare exomes 26/1,461,518 · genomes 8/152,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,420
African / African-American	0.00401%	24,963
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
South Asian	0.0022%	45,534
European (non-Finnish)	0.00203%	49,160
Admixed American	0.00167%	59,960
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Arg1075Cys
Coding: c.3223C>T
MANE Select: NM_001184785
Type: single nucleotide variant
Location: chr10:34269853 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.37 · 1 PDB
Residue 1078 UniProt numbering: the 'interaction with frmd4a' region

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

Similar variants

PARD3 p.Arg1075His Uncertain significance ★ ⚠ same residue
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
PARD3 p.Ala1062Thr 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-arg1075cys (accessed [today's date]).

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