Is SC5D p.Arg6Pro (c.17G>C) pathogenic?

SC5D p.Arg6Pro (c.17G>C) is classified Uncertain significance in SC5D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.6749); Very rare (popmax 0.00267%, afr).

How common is SC5D p.Arg6Pro (c.17G>C) in the general population?

SC5D p.Arg6Pro (c.17G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SC5D p.Arg6Pro (c.17G>C)?

AlphaMissense predicts likely pathogenic (score 0.6749) — an in-silico prediction, not a clinical call.

SC5D p.Arg6Pro

c.17G>C · rs370681255 · VCV1943675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6749	likely pathogenic
REVEL	0.485	indeterminate
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.22	acceptor loss, 26 bp away · masked 0 · deltas
Pangolin	Δ0.42	gain · loss 0.26 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP -2.9	GERP -3.9
Regional constraint	o/e 0.85	unconstrained · MANE · 4,133 bp · p 0.0035 · regional, not allelic
Overall
CADD	11.09	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 0.00267% African / African-American · 2/74,886 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,772 alleles · very rare exomes 1/1,461,654 · genomes 1/152,118 · joint denominator

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.Arg6Pro
Coding: c.17G>C
MANE Select: NM_006918
dbSNP: rs370681255
Type: single nucleotide variant
Location: chr11:121303392 (GRCh38)
Gene constraint: LOEUF 1.303 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.05

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

Similar variants

SC5D p.Arg6Cys Benign/Likely benign ★★ ⚠ 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
SC5D p.Val57Leu 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-arg6pro (accessed [today's date]).

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