Is ALG10 p.Arg416Cys (c.1246C>T) pathogenic?

ALG10 p.Arg416Cys (c.1246C>T) is classified Uncertain significance in ALG10 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely pathogenic (0.915); Very rare (popmax 0.005%, amr).

How common is ALG10 p.Arg416Cys (c.1246C>T) in the general population?

ALG10 p.Arg416Cys (c.1246C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ALG10 p.Arg416Cys (c.1246C>T)?

AlphaMissense predicts likely pathogenic (score 0.915) — an in-silico prediction, not a clinical call.

ALG10 p.Arg416Cys

c.1246C>T · rs762214045 · VCV2346409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.915	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -12.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 3.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 4,312 bp · p 0.0095 · regional, not allelic
Overall
CADD	29.4	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 0.005% Admixed American · 3/59,978 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000806% 13/1,613,722 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,993
Remaining individualsnot grpmax-eligible	0.0032%	31,238
South Asian	0.0022%	45,531
European (non-Finnish)	0.000509%	196,643

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: ALG10
Protein: p.Arg416Cys
Coding: c.1246C>T
MANE Select: NM_032834
dbSNP: rs762214045
Type: single nucleotide variant
Location: chr12:34026739 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.51

Full ALG10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG10 p.Arg416His Uncertain significance ★ ⚠ same residue
ALG10 p.Ser243= Benign ★★ same type
ALG10 p.Thr134= Benign ★★ same type
ALG10 p.Val269Ile Benign ★★ same type
ALG10 c.369+1G>T Likely pathogenic ★ same type
ALG10 p.Met61Val Likely pathogenic ★ ⚠ same type
ALG10 p.Ala11Asp Uncertain significance ★ ⚠ same type
ALG10 p.Ala11Thr 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/alg10-p-arg416cys (accessed [today's date]).

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