SEC31A p.Arg199=

Q: Is SEC31A p.Arg199= (c.597A>G) pathogenic?

SEC31A p.Arg199= (c.597A>G) is classified Benign in SEC31A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-26). Common (popmax 67.8%, amr) — too common for a highly-penetrant pathogenic allele; Associated with neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies.

Q: What condition is associated with SEC31A p.Arg199= (c.597A>G)?

SEC31A p.Arg199= (c.597A>G) is associated with neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies (ClinVar).

Q: How common is SEC31A p.Arg199= (c.597A>G) in the general population?

SEC31A p.Arg199= (c.597A>G) is common (popmax 67.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.597A>G · rs10025654 · VCV1332935

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 67.8%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies

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 -5.1	GERP -3.7
Overall
CADD	5.079	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.8% Admixed American · 39,995/59,012 alleles

Filtering AF 67.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 67%

Overall 54.1% 871,789/1,611,056 alleles · common exomes 802,775/1,458,962 · genomes 69,014/152,094 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	67.8%	1
Amishnot grpmax-eligible	61.4%	2
Finnishnot grpmax-eligible	60.9%	2
European (non-Finnish)	57.9%	2
Remaining individualsnot grpmax-eligible	50.7%	2
Ashkenazi Jewishnot grpmax-eligible	50%	2
Middle Eastern	44.1%	2
South Asian	37.6%	3
East Asian	30.5%	3
African / African-American	17.3%	6

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: SEC31A
Protein: p.Arg199=
Coding: c.597A>G
MANE Select: NM_001077207
dbSNP: rs10025654
Type: single nucleotide variant
Location: chr4:82874653 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 68.95 · 2 PDB
Residue 199: a turn; the 'interaction with sec13' region

Full SEC31A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEC31A p.Cys458Trp Uncertain significance ★★ ⚠ same condition
SEC31A c.1045-26G>T Benign ★★ same condition
SEC31A c.2154+36G>C Benign ★★ same condition
SEC31A c.2503-29C>A Benign ★★ same condition
SEC31A c.640-4T>G Benign ★★ same condition
SEC31A p.Gly336= Benign ★★ same condition
SEC31A p.Asp1114Glu Uncertain significance ★ ⚠ same condition
SEC31A p.Ala927fs Pathogenic same condition

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/sec31a-p-arg199 (accessed [today's date]).

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