Is SC5D p.Pro221= (c.663A>T) pathogenic?

SC5D p.Pro221= (c.663A>T) is classified Likely benign in SC5D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). Ultra-rare (popmax 0.0134%, eas).

How common is SC5D p.Pro221= (c.663A>T) in the general population?

SC5D p.Pro221= (c.663A>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

SC5D p.Pro221=

c.663A>T · rs376514394 · VCV2142384

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -3.9
Overall
CADD	1.024	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,896 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00112% 18/1,614,038 alleles · ultra-rare exomes 13/1,461,844 · genomes 5/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,483
African / African-American	0.00934%	10,704
Remaining individualsnot grpmax-eligible	0.008%	12,497

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: SC5D
Protein: p.Pro221=
Coding: c.663A>T
MANE Select: NM_006918
dbSNP: rs376514394
Type: single nucleotide variant
Location: chr11:121307275 (GRCh38)
Gene constraint: LOEUF 1.303 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.05
Residue 221: the fatty acid hydroxylase domain

Full SC5D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SC5D p.Pro221Leu Uncertain significance ★ ⚠ same residue
SC5D p.Pro221Ser Uncertain significance ★ ⚠ same residue
SC5D p.Arg277Cys Uncertain significance ★★ ⚠ same type
SC5D p.Asn292Ser Uncertain significance ★★ ⚠ same type
SC5D p.Asp59Asn Uncertain significance ★★ ⚠ same type
SC5D p.Lys148Glu Uncertain significance ★★ ⚠ same type
SC5D p.Met234Val Uncertain significance ★★ ⚠ same type
SC5D p.Tyr55Cys 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/sc5d-p-pro221 (accessed [today's date]).

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