Is SEC23B p.Ala717Ser (c.2149G>T) pathogenic?

SEC23B p.Ala717Ser (c.2149G>T) is classified Uncertain significance in SEC23B (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.2139); Very rare (popmax 0.00401%, afr).

How common is SEC23B p.Ala717Ser (c.2149G>T) in the general population?

SEC23B p.Ala717Ser (c.2149G>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about SEC23B p.Ala717Ser (c.2149G>T)?

AlphaMissense predicts likely benign (score 0.2139) — an in-silico prediction, not a clinical call.

SEC23B p.Ala717Ser

c.2149G>T · VCV4448160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2139 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2139	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -10.84	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.53	acceptor loss · deltas
Pangolin	Δ0.50	loss · gain 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 50 kb · p 0.036 · regional, not allelic
Overall
CADD	25.9	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 0.00401% African / African-American · 3/74,828 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,612,944 alleles · very rare exomes 1/1,460,936 · genomes 4/152,008 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,943
East Asian	0.00223%	44,872
South Asian	0.0011%	91,038

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: SEC23B
Protein: p.Ala717Ser
Coding: c.2149G>T
MANE Select: NM_006363
Type: single nucleotide variant
Location: chr20:18555108 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.41
Residue 717: a UniProt-annotated variant site (in cdan2)

Full SEC23B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEC23B p.Ala717= Likely benign ★ same residue
SEC23B p.Ala717fs Pathogenic/Likely pathogenic ★★ same residue
SEC23B c.1314+1G>A Likely pathogenic ★★ same type
SEC23B c.835-2A>G Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Ala524Val Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Arg14Trp Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Arg264Ter Pathogenic ★★ same type
SEC23B p.Arg313His Pathogenic/Likely pathogenic ★★ 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/sec23b-p-ala717ser (accessed [today's date]).

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