Is API5 p.Asp427His (c.1279G>C) pathogenic?

API5 p.Asp427His (c.1279G>C) is classified Uncertain significance in API5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1.

How common is API5 p.Asp427His (c.1279G>C) in the general population?

API5 p.Asp427His (c.1279G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about API5 p.Asp427His (c.1279G>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

API5 p.Asp427His

c.1279G>C · VCV4123268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 3% in API5
REVEL	0.521	indeterminate
SaProt	LLR -17.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.47	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.44	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 19 kb · p 2.4e-21 · regional, not allelic
Overall
CADD	32.0	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

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: API5
Protein: p.Asp427His
Coding: c.1279G>C
MANE Select: NM_001142930
Type: single nucleotide variant
Location: chr11:43335278 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 3 PDB
Residue 427: an α-helix

Full API5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

API5 p.Ala402Thr Uncertain significance ★ ⚠ same type
API5 p.Arg243Trp Uncertain significance ★ ⚠ same type
API5 p.Asn517His Uncertain significance ★ ⚠ same type
API5 p.Asp164Glu Uncertain significance ★ ⚠ same type
API5 p.Asp359His Uncertain significance ★ ⚠ same type
API5 p.Cys234Tyr Uncertain significance ★ ⚠ same type
API5 p.Glu215Gln Uncertain significance ★ ⚠ same type
API5 p.Glu329Asp 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/api5-p-asp427his (accessed [today's date]).

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