Is ANPEP p.His331Arg (c.992A>G) pathogenic?

ANPEP p.His331Arg (c.992A>G) is classified Uncertain significance in ANPEP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-05). AlphaMissense: likely benign (0.3166); Rare (popmax 0.181%, mid).

How common is ANPEP p.His331Arg (c.992A>G) in the general population?

ANPEP p.His331Arg (c.992A>G) is rare (popmax 0.181%, mid) (gnomAD).

What do computational predictors say about ANPEP p.His331Arg (c.992A>G)?

AlphaMissense predicts likely benign (score 0.3166) — an in-silico prediction, not a clinical call.

ANPEP p.His331Arg

c.992A>G · rs201350251 · VCV2349980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3166 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3166	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -8.61	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 5	GERP -0.14, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 21 kb · p 0.033 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.181% Middle Eastern · 11/6,062 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0787%

Overall 0.0173% 279/1,614,206 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.181%	551
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
European (non-Finnish)	0.0203%	4,937
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.00666%	15,006
South Asian	0.00549%	18,218
African / African-American	0.00266%	37,527

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: ANPEP
Protein: p.His331Arg
Coding: c.992A>G
MANE Select: NM_001150
dbSNP: rs201350251
Type: single nucleotide variant
Location: chr15:89804523 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.55 · 15 PDB
Residue 331: the 'metalloprotease' region; an α-helix

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

Similar variants

ANPEP c.1437+8C>G Benign ★★ same type
ANPEP c.1437+9C>G Benign ★★ same type
ANPEP p.Ala311Val Benign ★★ ⚠ same type
ANPEP p.Ala422Gly Likely benign ★★ ⚠ same type
ANPEP p.Ala671= Benign ★★ same type
ANPEP p.Glu770= Benign ★★ same type
ANPEP p.Leu100= Benign/Likely benign ★★ same type
ANPEP p.Leu258Ile Likely benign ★★ ⚠ 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/anpep-p-his331arg (accessed [today's date]).

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