Is ARHGDIG p.Pro35= (c.105G>A) pathogenic?

ARHGDIG p.Pro35= (c.105G>A) is classified Benign in ARHGDIG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 6.23%, afr) — too common for a highly-penetrant pathogenic allele.

ARHGDIG p.Pro35=

Q: How common is ARHGDIG p.Pro35= (c.105G>A) in the general population?

ARHGDIG p.Pro35= (c.105G>A) is common (popmax 6.23%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.105G>A · rs78288331 · VCV778577

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 6.23%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.31	GERP -2.8
Overall
CADD	13.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.23% African / African-American · 4,666/74,898 alleles

Filtering AF 6.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.02%

Overall 0.348% 5,593/1,606,690 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.23%	16
Middle Eastern	0.874%	114
Admixed American	0.625%	160
Remaining individualsnot grpmax-eligible	0.507%	197
South Asian	0.0221%	4,531
European (non-Finnish)	0.0143%	7,005

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: ARHGDIG
Protein: p.Pro35=
Coding: c.105G>A
MANE Select: NM_001176
dbSNP: rs78288331
Type: single nucleotide variant
Location: chr16:281777 (GRCh38)
Gene constraint: LOEUF 1.297 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.79

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

Similar variants

ARHGDIG p.Ala186Val Uncertain significance ★ ⚠ same type
ARHGDIG p.Ala190Val Uncertain significance ★ ⚠ same type
ARHGDIG p.Ala44Val Uncertain significance ★ ⚠ same type
ARHGDIG p.Ala50Gly Uncertain significance ★ ⚠ same type
ARHGDIG p.Ala50Val Uncertain significance ★ ⚠ same type
ARHGDIG p.Ala6Gly Uncertain significance ★ ⚠ same type
ARHGDIG p.Ala6Val Uncertain significance ★ ⚠ same type
ARHGDIG p.Arg156Gln 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/arhgdig-p-pro35 (accessed [today's date]).

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