Is APLN p.Pro29Ser (c.85C>T) pathogenic?

APLN p.Pro29Ser (c.85C>T) is classified Likely benign in APLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0623); Very rare (popmax 0.00886%, afr).

How common is APLN p.Pro29Ser (c.85C>T) in the general population?

APLN p.Pro29Ser (c.85C>T) is very rare (popmax 0.00886%, afr) (gnomAD).

What do computational predictors say about APLN p.Pro29Ser (c.85C>T)?

AlphaMissense predicts likely benign (score 0.0623) — an in-silico prediction, not a clinical call.

APLN p.Pro29Ser

c.85C>T · VCV4641646

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00886%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0623	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -1.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 6,001 bp · p 0.23 · regional, not allelic
Overall
CADD	6.985	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 0.00886% African / African-American · 5/56,432 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00218%

Overall 0.000513% 6/1,170,088 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00886%	11,286
Remaining individualsnot grpmax-eligible	0.00217%	46,008

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: APLN
Protein: p.Pro29Ser
Coding: c.85C>T
MANE Select: NM_017413
Type: single nucleotide variant
Location: chrX:129648775 (GRCh38)
Structure: AlphaFold pLDDT 67.45 · 5 PDB

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

Similar variants

APLN c.67+151A>G Benign ★★ same type
APLN c.-107T>C Benign ★★ same type
APLN c.-314T>C Benign ★★ same type
APLN c.*5+62C>T Benign ★★ same type
APLN p.Arg49Trp Uncertain significance ★ ⚠ same type
APLN p.Arg59Gln Uncertain significance ★ ⚠ same type
APLN p.Arg59Trp Uncertain significance ★ ⚠ same type
APLN p.Arg63His 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/apln-p-pro29ser (accessed [today's date]).

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