Is SP7 p.Arg337Cys (c.1009C>T) pathogenic?

SP7 p.Arg337Cys (c.1009C>T) is classified Uncertain significance in SP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-16). AlphaMissense: likely pathogenic (0.9951); Very rare (popmax 0.00333%, amr).

How common is SP7 p.Arg337Cys (c.1009C>T) in the general population?

SP7 p.Arg337Cys (c.1009C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about SP7 p.Arg337Cys (c.1009C>T)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

SP7 p.Arg337Cys

c.1009C>T · rs779183180 · VCV1921325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 6% in SP7
REVEL	0.58	indeterminate
SaProt	LLR -11.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,497 bp · p 0.16 · regional, not allelic
Overall
CADD	33.0	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 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00112% 18/1,613,818 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)	0.00119%	84,277
South Asian	0.0011%	91,090

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: SP7
Protein: p.Arg337Cys
Coding: c.1009C>T
MANE Select: NM_001173467
dbSNP: rs779183180
Type: single nucleotide variant
Location: chr12:53328433 (GRCh38)
Gene constraint: LOEUF 0.808 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 52.78

Full SP7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SP7 p.Arg337His Uncertain significance ★ ⚠ same residue
SP7 p.Ala2Val Uncertain significance ★★ ⚠ same type
SP7 p.Arg267Cys Uncertain significance ★★ ⚠ same type
SP7 p.Arg280Leu Uncertain significance ★★ ⚠ same type
SP7 p.Arg280Trp Uncertain significance ★★ ⚠ same type
SP7 p.Arg316His Uncertain significance ★★ ⚠ same type
SP7 p.Arg350Trp Uncertain significance ★★ ⚠ same type
SP7 p.Arg362His 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/sp7-p-arg337cys (accessed [today's date]).

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