Is STRA6 p.Ser46Arg (c.138C>G) pathogenic?

STRA6 p.Ser46Arg (c.138C>G) is classified Uncertain significance in STRA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-21). AlphaMissense: likely benign (0.1952); Ultra-rare (popmax 0.0294%, afr); Associated with Inborn genetic diseases.

What condition is associated with STRA6 p.Ser46Arg (c.138C>G)?

STRA6 p.Ser46Arg (c.138C>G) is associated with Inborn genetic diseases (ClinVar).

How common is STRA6 p.Ser46Arg (c.138C>G) in the general population?

STRA6 p.Ser46Arg (c.138C>G) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about STRA6 p.Ser46Arg (c.138C>G)?

AlphaMissense predicts likely benign (score 0.1952) — an in-silico prediction, not a clinical call.

STRA6 p.Ser46Arg

c.138C>G · rs140547600 · VCV2598191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1952	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	acceptor gain, 24 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -4.8	GERP -4.2
Regional constraint	o/e 0.91	unconstrained · MANE · 22 kb · p 0.0065 · regional, not allelic
Overall
CADD	0.018	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 0.0294% African / African-American · 22/74,930 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00186% 30/1,613,486 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,406
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Admixed American	0.00333%	30,004

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: STRA6
Protein: p.Ser46Arg
Coding: c.138C>G
MANE Select: NM_022369
dbSNP: rs140547600
Type: single nucleotide variant
Location: chr15:74197794 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.18

Full STRA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STRA6 p.Ala557Thr Uncertain significance ★★ ⚠ same condition
STRA6 p.Arg638His Uncertain significance ★★ ⚠ same condition
STRA6 p.Arg82Cys Uncertain significance ★★ ⚠ same condition
STRA6 p.Asp560Asn Uncertain significance ★★ ⚠ same condition
STRA6 p.His281Arg Uncertain significance ★★ ⚠ same condition
STRA6 p.Lys571Asn Uncertain significance ★★ same condition
STRA6 p.Met624Thr Uncertain significance ★★ ⚠ same condition
STRA6 p.Pro554Leu Uncertain significance ★★ ⚠ same condition

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/stra6-p-ser46arg (accessed [today's date]).

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