Is ALG12 p.Ser86Leu (c.257C>T) pathogenic?

ALG12 p.Ser86Leu (c.257C>T) is classified Uncertain significance in ALG12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-19). AlphaMissense: likely benign (0.1244); Ultra-rare (popmax 0.0133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALG12 p.Ser86Leu (c.257C>T)?

ALG12 p.Ser86Leu (c.257C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ALG12 p.Ser86Leu (c.257C>T) in the general population?

ALG12 p.Ser86Leu (c.257C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about ALG12 p.Ser86Leu (c.257C>T)?

AlphaMissense predicts likely benign (score 0.1244) — an in-silico prediction, not a clinical call.

ALG12 p.Ser86Leu

c.257C>T · rs911437496 · VCV2207252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1244 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1244	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.24, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	23.3	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 0.0133% African / African-American · 10/74,936 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00192% 31/1,613,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,494
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Admixed American	0.00167%	60,012
European (non-Finnish)	0.00153%	65,558

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: ALG12
Protein: p.Ser86Leu
Coding: c.257C>T
MANE Select: NM_024105
dbSNP: rs911437496
Type: single nucleotide variant
Location: chr22:49913423 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26

Full ALG12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALG12 p.Ser86= Likely benign ★ same residue
ALG12 p.Ala135Thr Uncertain significance ★★ ⚠ same condition
ALG12 p.Ala290Thr Uncertain significance ★★ ⚠ same condition
ALG12 p.Ala300Thr Uncertain significance ★★ ⚠ same condition
ALG12 p.Ala357Thr Uncertain significance ★★ ⚠ same condition
ALG12 p.Ala411Thr Uncertain significance ★★ ⚠ same condition
ALG12 p.Arg10Trp Uncertain significance ★★ ⚠ same condition
ALG12 p.Arg120Trp Uncertain significance ★★ ⚠ same condition

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/alg12-p-ser86leu (accessed [today's date]).

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