Is AP3S2 p.Leu71Val (c.211C>G) pathogenic?

AP3S2 p.Leu71Val (c.211C>G) is classified Uncertain significance in AP3S2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: likely pathogenic (0.9695); Very rare (popmax 0.0022%, sas).

How common is AP3S2 p.Leu71Val (c.211C>G) in the general population?

AP3S2 p.Leu71Val (c.211C>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about AP3S2 p.Leu71Val (c.211C>G)?

AlphaMissense predicts likely pathogenic (score 0.9695) — an in-silico prediction, not a clinical call.

AP3S2 p.Leu71Val

c.211C>G · VCV3404376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9695	likely pathogenic
REVEL	0.606	indeterminate
SaProt	LLR -13.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 58 kb · p 0.79 · regional, not allelic
Overall
CADD	25.0	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

Grpmax group 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000558% 9/1,614,090 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000508%	196,674

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: AP3S2
Protein: p.Leu71Val
Coding: c.211C>G
MANE Select: NM_005829
Type: single nucleotide variant
Location: chr15:89888583 (GRCh38)
Gene constraint: LOEUF 1.304 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.92

Full AP3S2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP3S2 p.Ala143Val Uncertain significance ★ ⚠ same type
AP3S2 p.Ala157Val Uncertain significance ★ ⚠ same type
AP3S2 p.Ala69Val Uncertain significance ★ ⚠ same type
AP3S2 p.Arg175Gln Uncertain significance ★ ⚠ same type
AP3S2 p.Arg18His Uncertain significance ★ ⚠ same type
AP3S2 p.Arg33Gly Uncertain significance ★ ⚠ same type
AP3S2 p.Arg66Gln Uncertain significance ★ ⚠ same type
AP3S2 p.Asn178His 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/ap3s2-p-leu71val (accessed [today's date]).

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