Is ATL1 p.Ala331Ser (c.991G>T) pathogenic?

ATL1 p.Ala331Ser (c.991G>T) is classified Uncertain significance in ATL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.2159); Very rare (popmax 0.00336%, sas).

How common is ATL1 p.Ala331Ser (c.991G>T) in the general population?

ATL1 p.Ala331Ser (c.991G>T) is very rare (popmax 0.00336%, sas) (gnomAD).

What do computational predictors say about ATL1 p.Ala331Ser (c.991G>T)?

AlphaMissense predicts likely benign (score 0.2159) — an in-silico prediction, not a clinical call.

ATL1 p.Ala331Ser

c.991G>T · rs1175428745 · VCV1298580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2159	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -4.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.27	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.28	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,372 bp · p 0.19 · regional, not allelic
Overall
CADD	25.9	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 0.00336% South Asian · 3/89,232 alleles

Filtering AF 0.000893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000448%

Overall 0.000282% 4/1,416,962 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00336%	29,744
European (non-Finnish)	8.76e-05%	1,141,392

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: ATL1
Protein: p.Ala331Ser
Coding: c.991G>T
MANE Select: NM_015915
dbSNP: rs1175428745
Type: single nucleotide variant
Location: chr14:50621843 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.36 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 14 PDB
Residue 331: an α-helix

Full ATL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATL1 p.Arg217Gln Pathogenic/Likely pathogenic ★★ same type
ATL1 p.Arg239Cys Pathogenic/Likely pathogenic ★★ same type
ATL1 p.Arg239His Likely pathogenic ★★ same type
ATL1 p.Arg403Pro Likely pathogenic ★★ same type
ATL1 p.Arg415Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
ATL1 p.Arg416Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
ATL1 p.Arg495Trp Pathogenic/Likely pathogenic ★★ same type
ATL1 p.Arg501Ter Pathogenic ★★ 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/atl1-p-ala331ser (accessed [today's date]).

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