Is SCLY p.Ser97Phe (c.290C>T) pathogenic?

SCLY p.Ser97Phe (c.290C>T) is classified Uncertain significance in SCLY (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely pathogenic (0.9465); Very rare (popmax 0.00224%, eas).

How common is SCLY p.Ser97Phe (c.290C>T) in the general population?

SCLY p.Ser97Phe (c.290C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about SCLY p.Ser97Phe (c.290C>T)?

AlphaMissense predicts likely pathogenic (score 0.9465) — an in-silico prediction, not a clinical call.

SCLY p.Ser97Phe

c.290C>T · VCV3438064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9465	likely pathogenic · top 8% in SCLY
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -11.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 37 kb · p 0.42 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00224% East Asian · 1/44,604 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000435% 7/1,608,004 alleles · very rare exomes 7/1,455,692 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,604
European (non-Finnish)	0.00051%	196,087

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.Ser97Phe
Coding: c.290C>T
MANE Select: NM_016510
Type: single nucleotide variant
Location: chr2:238068152 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.14 · 2 PDB
Residue 97: a β-strand

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-ser97phe (accessed [today's date]).

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