Is ACSS1 p.Pro668Ser (c.2002C>T) pathogenic?

ACSS1 p.Pro668Ser (c.2002C>T) is classified Uncertain significance in ACSS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: likely benign (0.1317); Very rare (popmax 0.00667%, amr).

How common is ACSS1 p.Pro668Ser (c.2002C>T) in the general population?

ACSS1 p.Pro668Ser (c.2002C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ACSS1 p.Pro668Ser (c.2002C>T)?

AlphaMissense predicts likely benign (score 0.1317) — an in-silico prediction, not a clinical call.

ACSS1 p.Pro668Ser

c.2002C>T · rs771864039 · VCV2367754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1317	likely benign
REVEL	0.331	indeterminate
SaProt	LLR -3.34	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 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 15 kb · p 3.4e-10 · regional, not allelic
Overall
CADD	24.1	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 0.00667% Admixed American · 4/60,010 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000805% 13/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000678%	147,504

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: ACSS1
Protein: p.Pro668Ser
Coding: c.2002C>T
MANE Select: NM_032501
dbSNP: rs771864039
Type: single nucleotide variant
Location: chr20:25007830 (GRCh38)
Gene constraint: LOEUF 0.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.07 · 9 PDB

Full ACSS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSS1 p.Val479Ile Benign ★★ ⚠ same type
ACSS1 p.Ala181Gly Uncertain significance ★ ⚠ same type
ACSS1 p.Ala211Val Uncertain significance ★ ⚠ same type
ACSS1 p.Ala279Thr Uncertain significance ★ ⚠ same type
ACSS1 p.Ala316Thr Uncertain significance ★ ⚠ same type
ACSS1 p.Ala37Glu Uncertain significance ★ ⚠ same type
ACSS1 p.Ala454Thr Uncertain significance ★ ⚠ same type
ACSS1 p.Ala602Val 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/acss1-p-pro668ser (accessed [today's date]).

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