Is RYK p.Ala49= (c.147C>T) pathogenic?

RYK p.Ala49= (c.147C>T) is classified Benign in RYK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-11). Common (popmax 51.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with RYK-related disorder.

What condition is associated with RYK p.Ala49= (c.147C>T)?

RYK p.Ala49= (c.147C>T) is associated with RYK-related disorder (ClinVar).

RYK p.Ala49=

Q: How common is RYK p.Ala49= (c.147C>T) in the general population?

RYK p.Ala49= (c.147C>T) is common (popmax 51.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.147C>T · rs139860270 · VCV3048012

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 51.3%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

RYK-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.051	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.1, phastCons 1
Overall
CADD	11.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 51.3% East Asian · 15,667/30,558 alleles

Filtering AF 50.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.3%

Overall 13.5% 168,193/1,246,878 alleles · common exomes 146,474/1,095,566 · genomes 21,719/151,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	51.3%	2
Admixed American	19.6%	5
South Asian	16.3%	6
Remaining individualsnot grpmax-eligible	15.1%	7
Finnishnot grpmax-eligible	14.4%	7
Middle Eastern	13.8%	7
African / African-American	13.2%	8
European (non-Finnish)	12.1%	8
Amishnot grpmax-eligible	10%	10
Ashkenazi Jewishnot grpmax-eligible	9.47%	11

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: RYK
Protein: p.Ala49=
Coding: c.147C>T
MANE Select: NM_002958
dbSNP: rs139860270
Type: single nucleotide variant
Location: chr3:134250508 (GRCh38)
Gene constraint: LOEUF 0.457 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 80.54 · 1 PDB

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

Disease context

RYK-related disorder

Similar variants

RYK p.Ile325Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
RYK p.Leu273= Uncertain significance ★ same condition
RYK p.Leu313= Likely benign ★ same condition
RYK p.Lys192Arg Likely benign ★ same condition
RYK p.Pro50Leu Likely benign ★ same condition
RYK p.Ala4fs Benign ★★ same condition
RYK c.233-4C>G Benign ★★ same type
RYK p.Arg51Trp Benign ★★ 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/ryk-p-ala49 (accessed [today's date]).

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