Is ACSF2 p.Ser375Leu (c.1124C>T) pathogenic?

ACSF2 p.Ser375Leu (c.1124C>T) is classified Uncertain significance in ACSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: likely benign (0.1776); Very rare (popmax 0.00288%, nfe).

How common is ACSF2 p.Ser375Leu (c.1124C>T) in the general population?

ACSF2 p.Ser375Leu (c.1124C>T) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about ACSF2 p.Ser375Leu (c.1124C>T)?

AlphaMissense predicts likely benign (score 0.1776) — an in-silico prediction, not a clinical call.

ACSF2 p.Ser375Leu

c.1124C>T · rs768330040 · VCV2274404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1776	likely benign
REVEL	0.445	indeterminate
SaProt	LLR -13.80	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 48 kb · p 5.1e-07 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00288% European (non-Finnish) · 34/1,180,028 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00223% 36/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,707
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: ACSF2
Protein: p.Ser375Leu
Coding: c.1124C>T
MANE Select: NM_025149
dbSNP: rs768330040
Type: single nucleotide variant
Location: chr17:50463895 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.40

Full ACSF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHAD p.Leu226= Benign ★★ same type
CHAD p.Pro349= Benign ★★ same type
CHAD p.Thr350Ile Benign ★★ ⚠ same type
ACSF2 p.Ala112Ser Uncertain significance ★ ⚠ same type
ACSF2 p.Ala15Pro Uncertain significance ★ ⚠ same type
ACSF2 p.Ala15Thr Uncertain significance ★ ⚠ same type
ACSF2 p.Ala160Pro Uncertain significance ★ ⚠ same type
ACSF2 p.Ala160Val 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/acsf2-p-ser375leu (accessed [today's date]).

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