Is SEC23B p.Ala329Pro (c.985G>C) pathogenic?

SEC23B p.Ala329Pro (c.985G>C) is classified Uncertain significance in SEC23B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-22). AlphaMissense: likely pathogenic (0.9913); Ultra-rare (popmax 0.0329%, mid); Associated with congenital dyserythropoietic anemia type 2.

What condition is associated with SEC23B p.Ala329Pro (c.985G>C)?

SEC23B p.Ala329Pro (c.985G>C) is associated with congenital dyserythropoietic anemia type 2, Cowden syndrome 7 (ClinVar).

How common is SEC23B p.Ala329Pro (c.985G>C) in the general population?

SEC23B p.Ala329Pro (c.985G>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Congenital dyserythropoietic anemia type II inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SEC23B p.Ala329Pro (c.985G>C)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

SEC23B p.Ala329Pro

c.985G>C · rs143417821 · VCV2102765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital dyserythropoietic anemia type 2

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic · top 9% in SEC23B
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -15.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 50 kb · p 0.036 · regional, not allelic
Overall
CADD	28.7	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00994%

Overall 0.00954% 154/1,614,032 alleles · ultra-rare exomes 147/1,461,856 · genomes 7/152,176 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.0122%	8,195
African / African-American	0.004%	24,972
Remaining individualsnot grpmax-eligible	0.0032%	31,241
East Asian	0.00223%	44,898
South Asian	0.0022%	45,545

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.Ala329Pro
Coding: c.985G>C
MANE Select: NM_006363
dbSNP: rs143417821
Type: single nucleotide variant
Location: chr20:18526523 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.41

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

Disease context

congenital dyserythropoietic anemia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cowden syndrome 7

For Congenital dyserythropoietic anemia type II (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

SEC23B p.Ala329Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
SEC23B p.Ala329fs Pathogenic ★ same residue
SEC23B c.1314+1G>A Likely pathogenic ★★ same condition
SEC23B c.835-2A>G Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Ala524Val Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Arg14Trp Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Arg264Ter Pathogenic ★★ same condition
SEC23B p.Arg313His Pathogenic/Likely 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/sec23b-p-ala329pro (accessed [today's date]).

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