Is NUDCD3 p.Arg235His (c.704G>A) pathogenic?

NUDCD3 p.Arg235His (c.704G>A) is classified Uncertain significance in NUDCD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely benign (0.0609); Very rare (popmax 0.005%, amr).

How common is NUDCD3 p.Arg235His (c.704G>A) in the general population?

NUDCD3 p.Arg235His (c.704G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about NUDCD3 p.Arg235His (c.704G>A)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

NUDCD3 p.Arg235His

c.704G>A · rs142257577 · VCV2320328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -7.54	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 0.15	phastCons 0.006
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	17.04	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 0.005% Admixed American · 3/59,984 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00161% 26/1,613,852 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
East Asian	0.00446%	22,441
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00144%	69,411
African / African-American	0.00134%	74,856
South Asian	0.0011%	91,062

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: NUDCD3
Protein: p.Arg235His
Coding: c.704G>A
MANE Select: NM_015332
dbSNP: rs142257577
Type: single nucleotide variant
Location: chr7:44404522 (GRCh38)
Gene constraint: LOEUF 0.492 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 80.39 · 1 PDB
Residue 235: the cs domain; a UniProt-annotated variant site (in); a β-strand

Full NUDCD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NUDCD3 p.His313Pro Likely pathogenic ★ same type
NUDCD3 p.Ala103Thr Uncertain significance ★ ⚠ same type
NUDCD3 p.Ala103Val Uncertain significance ★ ⚠ same type
NUDCD3 p.Ala159Pro Uncertain significance ★ ⚠ same type
NUDCD3 p.Ala303Thr Uncertain significance ★ ⚠ same type
NUDCD3 p.Ala5Ser Uncertain significance ★ ⚠ same type
NUDCD3 p.Ala6Val Uncertain significance ★ ⚠ same type
NUDCD3 p.Arg292Gly 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/nudcd3-p-arg235his (accessed [today's date]).

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