Is ACSF2 p.Arg443Trp (c.1327C>T) pathogenic?

ACSF2 p.Arg443Trp (c.1327C>T) is classified Uncertain significance in ACSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.1643); Very rare (popmax 0.00297%, nfe).

How common is ACSF2 p.Arg443Trp (c.1327C>T) in the general population?

ACSF2 p.Arg443Trp (c.1327C>T) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about ACSF2 p.Arg443Trp (c.1327C>T)?

AlphaMissense predicts likely benign (score 0.1643) — an in-silico prediction, not a clinical call.

ACSF2 p.Arg443Trp

c.1327C>T · VCV4000234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1643	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -13.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP 0.16, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 48 kb · p 5.1e-07 · regional, not allelic
Overall
CADD	25.3	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 0.00297% European (non-Finnish) · 35/1,179,176 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00261% 42/1,611,986 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,214
Finnishnot grpmax-eligible	0.00313%	31,903
European (non-Finnish)grpmax	0.00297%	33,691
East Asian	0.00224%	44,656
African / African-American	0.00133%	74,930
South Asian	0.0011%	90,752

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg443Trp
Coding: c.1327C>T
MANE Select: NM_025149
Type: single nucleotide variant
Location: chr17:50472431 (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

ACSF2 p.Arg443Gln Likely benign ★ ⚠ same residue
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

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-arg443trp (accessed [today's date]).

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