Is SCLY p.Lys89Asn (c.267A>T) pathogenic?

SCLY p.Lys89Asn (c.267A>T) is classified Uncertain significance in SCLY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely benign (0.2086); Very rare (popmax 0.00554%, sas).

How common is SCLY p.Lys89Asn (c.267A>T) in the general population?

SCLY p.Lys89Asn (c.267A>T) is very rare (popmax 0.00554%, sas) (gnomAD).

What do computational predictors say about SCLY p.Lys89Asn (c.267A>T)?

AlphaMissense predicts likely benign (score 0.2086) — an in-silico prediction, not a clinical call.

SCLY p.Lys89Asn

c.267A>T · VCV3793108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00554%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2086	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.1	GERP -4.1
Regional constraint	o/e 0.97	unconstrained · MANE · 37 kb · p 0.42 · regional, not allelic
Overall
CADD	1.427	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 0.00554% South Asian · 5/90,320 alleles

Filtering AF 0.00212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.000683% 11/1,611,458 alleles · very rare exomes 9/1,459,122 · genomes 2/152,336 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00554%	18,064
African / African-American	0.004%	24,986
European (non-Finnish)	0.000254%	392,960

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: SCLY
Protein: p.Lys89Asn
Coding: c.267A>T
MANE Select: NM_016510
Type: single nucleotide variant
Location: chr2:238068129 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.14 · 2 PDB

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

Similar variants

SCLY c.612+7C>T Benign ★★ same type
SCLY p.Ile86Met Benign ★★ same type
SCLY p.Phe276Ser Benign ★★ same type
SCLY p.Val326Ile Benign ★★ same type
SCLY p.Ala161Gly Uncertain significance ★ ⚠ same type
SCLY p.Ala183Val Uncertain significance ★ ⚠ same type
SCLY p.Ala235Ser Uncertain significance ★ ⚠ same type
SCLY p.Ala267Thr 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/scly-p-lys89asn (accessed [today's date]).

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