Is PFKL p.Arg95Ser (c.285G>C) pathogenic?

PFKL p.Arg95Ser (c.285G>C) is classified Uncertain significance in PFKL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely pathogenic (0.7165); Very rare (popmax 0.00272%, afr).

How common is PFKL p.Arg95Ser (c.285G>C) in the general population?

PFKL p.Arg95Ser (c.285G>C) is very rare (popmax 0.00272%, afr) (gnomAD).

What do computational predictors say about PFKL p.Arg95Ser (c.285G>C)?

AlphaMissense predicts likely pathogenic (score 0.7165) — an in-silico prediction, not a clinical call.

PFKL p.Arg95Ser

c.285G>C · rs866116296 · VCV2243046

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7165	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -11.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -3.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 27 kb · p 0.008 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00272% African / African-American · 2/73,654 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000314% 5/1,590,148 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00272%	36,827
European (non-Finnish)	0.000257%	389,665

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: PFKL
Protein: p.Arg95Ser
Coding: c.285G>C
MANE Select: NM_002626
dbSNP: rs866116296
Type: single nucleotide variant
Location: chr21:44312152 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.53 · 5 PDB
Residue 95: the 'n-terminal catalytic pfk domain 1' region; an α-helix

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

Similar variants

PFKL p.Arg513Cys Uncertain significance ★★ ⚠ same type
PFKL p.Glu738Lys Uncertain significance ★★ ⚠ same type
PFKL p.Pro332Leu Uncertain significance ★★ ⚠ same type
PFKL p.Val59Met Uncertain significance ★★ ⚠ same type
PFKL c.747+7G>A Benign ★★ same type
PFKL p.Ala320= Likely benign ★★ same type
PFKL p.Arg621= Benign ★★ same type
PFKL p.Asp237Val Benign ★★ ⚠ 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/pfkl-p-arg95ser (accessed [today's date]).

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