Is SCLY p.Phe276Ser (c.827T>C) pathogenic?

SCLY p.Phe276Ser (c.827T>C) is classified Benign in SCLY (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-29). AlphaMissense: likely benign (0.109); Common (popmax 8.98%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about SCLY p.Phe276Ser (c.827T>C)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

SCLY p.Phe276Ser

Q: How common is SCLY p.Phe276Ser (c.827T>C) in the general population?

SCLY p.Phe276Ser (c.827T>C) is common (popmax 8.98%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.827T>C · rs35637307 · VCV775836

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.98%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.403	indeterminate
SaProt	LLR 0.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.97	GERP -0.17
Regional constraint	o/e 0.97	unconstrained · MANE · 37 kb · p 0.42 · regional, not allelic
Overall
CADD	1.086	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 8.98% African / African-American · 6,733/74,942 alleles

Filtering AF 8.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.73%

Overall 0.468% 7,561/1,613,952 alleles · common exomes 3,640/1,461,700 · genomes 3,921/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.98%	11
Remaining individualsnot grpmax-eligible	0.602%	166
Admixed American	0.46%	217
Middle Eastern	0.264%	379
South Asian	0.0209%	4,794
European (non-Finnish)	0.012%	8,368

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.Phe276Ser
Coding: c.827T>C
MANE Select: NM_016510
dbSNP: rs35637307
Type: single nucleotide variant
Location: chr2:238083297 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.14 · 2 PDB
Residue 276: a turn; a UniProt-annotated variant site (in)

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.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
SCLY p.Ala309Gly 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-phe276ser (accessed [today's date]).

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