Is SP9 p.Ala462= (c.1386A>G) pathogenic?

SP9 p.Ala462= (c.1386A>G) is classified Likely benign in SP9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-04). Common (popmax 5.85%, mid) — too common for a highly-penetrant pathogenic allele.

SP9 p.Ala462=

Q: How common is SP9 p.Ala462= (c.1386A>G) in the general population?

SP9 p.Ala462= (c.1386A>G) is common (popmax 5.85%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1386A>G · rs368984751 · VCV770876

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 5.85%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	1.241	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.85% Middle Eastern · 238/4,068 alleles

Filtering AF 5.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.45%

Overall 2.45% 29,360/1,196,440 alleles · common exomes 24,014/1,051,922 · genomes 5,346/144,518 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	5.99%	17
Middle Easterngrpmax	5.85%	17
African / African-American	5.67%	18
Amishnot grpmax-eligible	4.35%	23
Admixed American	3.06%	33
Remaining individualsnot grpmax-eligible	2.64%	38
European (non-Finnish)	2.3%	43
South Asian	1.65%	61
Finnishnot grpmax-eligible	0.939%	107
East Asian	0.241%	415

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SP9
Protein: p.Ala462=
Coding: c.1386A>G
MANE Select: NM_001145250
dbSNP: rs368984751
Type: single nucleotide variant
Location: chr2:174337471 (GRCh38)
Gene constraint: LOEUF 0.731 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 49.04

Full SP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SP9 p.Ser112Ala Uncertain significance ★★ ⚠ same type
SP9 p.Glu378Gly Pathogenic ★ same type
SP9 p.Ser82Ter Pathogenic ★ same type
SP9 p.Ala176Val Uncertain significance ★ ⚠ same type
SP9 p.Ala241Ser Uncertain significance ★ ⚠ same type
SP9 p.Ala242Thr Uncertain significance ★ ⚠ same type
SP9 p.Ala393Ser Uncertain significance ★ ⚠ same type
SP9 p.Ala452Val 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/sp9-p-ala462 (accessed [today's date]).

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