Is ALS2CL p.Ser636Phe (c.1907C>T) pathogenic?

ALS2CL p.Ser636Phe (c.1907C>T) is classified Uncertain significance in ALS2CL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.1744); Very rare (popmax 8.48e-05%, nfe).

How common is ALS2CL p.Ser636Phe (c.1907C>T) in the general population?

ALS2CL p.Ser636Phe (c.1907C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ALS2CL p.Ser636Phe (c.1907C>T)?

AlphaMissense predicts likely benign (score 0.1744) — an in-silico prediction, not a clinical call.

ALS2CL p.Ser636Phe

c.1907C>T · rs2528671157 · VCV3114248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1744	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.71 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.1	GERP 0.24, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 18 kb · p 0.075 · regional, not allelic
Overall
CADD	24.0	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 8.48e-05% European (non-Finnish) · 1/1,179,866 alleles

Overall 6.84e-05% 1/1,461,448 alleles · very rare

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: ALS2CL
Protein: p.Ser636Phe
Coding: c.1907C>T
MANE Select: NM_147129
dbSNP: rs2528671157
Type: single nucleotide variant
Location: chr3:46676873 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.50

Full ALS2CL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALS2CL p.Ala207Ser Uncertain significance ★ ⚠ same type
ALS2CL p.Ala212Thr Uncertain significance ★ ⚠ same type
ALS2CL p.Ala343Thr Uncertain significance ★ ⚠ same type
ALS2CL p.Ala35Val Uncertain significance ★ ⚠ same type
ALS2CL p.Ala512Val Uncertain significance ★ ⚠ same type
ALS2CL p.Ala701Thr Uncertain significance ★ ⚠ same type
ALS2CL p.Ala713Thr Uncertain significance ★ ⚠ same type
ALS2CL p.Arg11Trp 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/als2cl-p-ser636phe (accessed [today's date]).

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