Is RIPPLY2 p.Ala4= (c.12G>A) pathogenic?

RIPPLY2 p.Ala4= (c.12G>A) is classified Benign in RIPPLY2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 57.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with spondylocostal dysostosis 6, autosomal recessive.

What condition is associated with RIPPLY2 p.Ala4= (c.12G>A)?

RIPPLY2 p.Ala4= (c.12G>A) is associated with spondylocostal dysostosis 6, autosomal recessive (ClinVar).

RIPPLY2 p.Ala4=

Q: How common is RIPPLY2 p.Ala4= (c.12G>A) in the general population?

RIPPLY2 p.Ala4= (c.12G>A) is common (popmax 57.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.12G>A · rs9353143 · VCV1165051

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 57.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

spondylocostal dysostosis 6, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -4.3
Overall
CADD	3.383	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 57.8% African / African-American · 42,125/72,864 alleles

Filtering AF 57.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 57.2%

Overall 11.6% 179,488/1,542,804 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	57.8%	2
Admixed American	31.9%	3
East Asian	24.3%	4
Amishnot grpmax-eligible	14%	7
Remaining individualsnot grpmax-eligible	13.2%	8
Finnishnot grpmax-eligible	11.4%	9
Middle Eastern	10.9%	9
Ashkenazi Jewishnot grpmax-eligible	7.78%	13
European (non-Finnish)	7.75%	13
South Asian	6.64%	15

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: RIPPLY2
Protein: p.Ala4=
Coding: c.12G>A
MANE Select: NM_001009994
dbSNP: rs9353143
Type: single nucleotide variant
Location: chr6:83853428 (GRCh38)
Gene constraint: LOEUF 1.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.67
Residue 4: the 'disordered' region

Full RIPPLY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondylocostal dysostosis 6, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIPPLY2 c.240-4T>G Conflicting classifications of pathogenicity ★ same condition
RIPPLY2 p.Arg80Ter Conflicting classifications of pathogenicity ★ same condition
RIPPLY2 p.Ala14Ser Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Ala14Thr Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Ala34Thr Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Glu118Lys Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Gly9Cys Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Met59Thr 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/ripply2-p-ala4 (accessed [today's date]).

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