Is ALS2 p.Ser776Gly (c.2326A>G) pathogenic?

ALS2 p.Ser776Gly (c.2326A>G) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-22). AlphaMissense: likely benign (0.0654); Very rare (popmax 0.00267%, afr).

How common is ALS2 p.Ser776Gly (c.2326A>G) in the general population?

ALS2 p.Ser776Gly (c.2326A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ALS2 p.Ser776Gly (c.2326A>G)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

ALS2 p.Ser776Gly

c.2326A>G · rs778099581 · VCV995262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.41	donor gain · deltas
Pangolin	Δ0.21	loss · gain 0.10 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 2.3	GERP 0.57, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	22.5	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 0.00267% African / African-American · 2/74,916 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00124% 20/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,458
Admixed American	0.00167%	59,996
Finnishnot grpmax-eligible	0.00156%	64,012
European (non-Finnish)	0.00136%	73,752

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: ALS2
Protein: p.Ser776Gly
Coding: c.2326A>G
MANE Select: NM_020919
dbSNP: rs778099581
Type: single nucleotide variant
Location: chr2:201741699 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 776: the dh domain

Full ALS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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ALS2 p.Ala573Glu Likely pathogenic ★★ same type
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same type
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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/als2-p-ser776gly (accessed [today's date]).

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