Is SCTR p.Arg299His (c.896G>A) pathogenic?

SCTR p.Arg299His (c.896G>A) is classified Uncertain significance in SCTR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely benign (0.285); Rare (popmax 0.248%, mid).

How common is SCTR p.Arg299His (c.896G>A) in the general population?

SCTR p.Arg299His (c.896G>A) is rare (popmax 0.248%, mid) (gnomAD).

What do computational predictors say about SCTR p.Arg299His (c.896G>A)?

AlphaMissense predicts likely benign (score 0.285) — an in-silico prediction, not a clinical call.

SCTR p.Arg299His

c.896G>A · rs376021809 · VCV2256706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.285 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.248%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.285	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 84 kb · p 0.62 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.248% Middle Eastern · 15/6,048 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.0134% 215/1,608,636 alleles · rare exomes 191/1,456,286 · genomes 24/152,350 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.439%	228
Middle Easterngrpmax	0.248%	403
African / African-American	0.02%	5,001
Remaining individualsnot grpmax-eligible	0.0193%	5,192
South Asian	0.0156%	6,418
European (non-Finnish)	0.0126%	7,950
Admixed American	0.00835%	11,970
East Asian	0.00446%	22,417

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SCTR
Protein: p.Arg299His
Coding: c.896G>A
MANE Select: NM_002980
dbSNP: rs376021809
Type: single nucleotide variant
Location: chr2:119452035 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.18 · 3 PDB
Residue 299: an α-helix

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

Similar variants

SCTR c.851+10C>T Benign ★★ same type
SCTR p.Ala292Thr Likely benign ★★ same type
SCTR p.Asp110Asn Benign ★★ same type
SCTR p.Cys208= Benign ★★ same type
SCTR p.Leu190= Benign ★★ same type
SCTR p.Pro415= Benign ★★ same type
SCTR p.Ala245Thr Uncertain significance ★ ⚠ same type
SCTR p.Ala375Val 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/sctr-p-arg299his (accessed [today's date]).

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