Is APLN p.His71Pro (c.212A>C) pathogenic?

APLN p.His71Pro (c.212A>C) is classified Uncertain significance in APLN (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.773); Absent from gnomAD v4.1.

How common is APLN p.His71Pro (c.212A>C) in the general population?

APLN p.His71Pro (c.212A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APLN p.His71Pro (c.212A>C)?

AlphaMissense predicts likely pathogenic (score 0.773) — an in-silico prediction, not a clinical call.

APLN p.His71Pro

c.212A>C · VCV4839312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.773 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.773	likely pathogenic
REVEL	0.55	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 6,001 bp · p 0.23 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APLN
Protein: p.His71Pro
Coding: c.212A>C
MANE Select: NM_017413
Type: single nucleotide variant
Location: chrX:129648648 (GRCh38)
Structure: AlphaFold pLDDT 67.45 · 5 PDB
Residue 71: a β-strand; the 'disordered' region

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-his71pro (accessed [today's date]).

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