Is SP7 p.Arg280Trp (c.838C>T) pathogenic?

SP7 p.Arg280Trp (c.838C>T) is classified Uncertain significance in SP7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-19). AlphaMissense: likely pathogenic (0.865); Very rare (popmax 0.0044%, sas).

How common is SP7 p.Arg280Trp (c.838C>T) in the general population?

SP7 p.Arg280Trp (c.838C>T) is very rare (popmax 0.0044%, sas) (gnomAD).

What do computational predictors say about SP7 p.Arg280Trp (c.838C>T)?

AlphaMissense predicts likely pathogenic (score 0.865) — an in-silico prediction, not a clinical call.

SP7 p.Arg280Trp

c.838C>T · rs760112039 · VCV1478502

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.865	likely pathogenic
REVEL	0.277	benign-leaning
SaProt	LLR -13.08	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 0.81, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,497 bp · p 0.16 · regional, not allelic
Overall
CADD	27.2	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 0.0044% South Asian · 4/90,956 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00155% 25/1,609,944 alleles · very rare exomes 25/1,457,652 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,739
Admixed American	0.00167%	59,938
European (non-Finnish)	0.00161%	61,951
African / African-American	0.00133%	74,942

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.Arg280Trp
Coding: c.838C>T
MANE Select: NM_001173467
dbSNP: rs760112039
Type: single nucleotide variant
Location: chr12:53328604 (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.Arg280Leu Uncertain significance ★★ ⚠ same residue
SP7 p.Arg280Gln Uncertain significance ★ ⚠ same residue
SP7 p.Ala2Val Uncertain significance ★★ ⚠ same type
SP7 p.Arg267Cys 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
SP7 p.Arg365Ter 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-arg280trp (accessed [today's date]).

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