Is CD14 p.Val333Ile (c.997G>A) pathogenic?

CD14 p.Val333Ile (c.997G>A) is classified Uncertain significance in CD14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely benign (0.0949); Ultra-rare (popmax 0.0329%, mid).

How common is CD14 p.Val333Ile (c.997G>A) in the general population?

CD14 p.Val333Ile (c.997G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CD14 p.Val333Ile (c.997G>A)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

CD14 p.Val333Ile

c.997G>A · VCV3997974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP -1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,212 bp · p 0.37 · regional, not allelic
Overall
CADD	9.364	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00242% 39/1,613,874 alleles · ultra-rare exomes 37/1,461,708 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
African / African-American	0.0307%	3,257
Remaining individualsnot grpmax-eligible	0.0208%	4,806
Admixed American	0.00167%	59,996

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: CD14
Protein: p.Val333Ile
Coding: c.997G>A
MANE Select: NM_000591
Type: single nucleotide variant
Location: chr5:140631987 (GRCh38)
Gene constraint: LOEUF 1.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.36 · 1 PDB
Residue 333: the 'required for response to bacterial lipopolysaccharide (lps)' region

Full CD14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD14 p.Ala114Thr Uncertain significance ★ ⚠ same type
CD14 p.Ala143Gly Uncertain significance ★ ⚠ same type
CD14 p.Ala184Thr Uncertain significance ★ ⚠ same type
CD14 p.Ala269Thr Uncertain significance ★ ⚠ same type
CD14 p.Ala75Gly Uncertain significance ★ ⚠ same type
CD14 p.Ala98Ser Uncertain significance ★ ⚠ same type
CD14 p.Arg111His Uncertain significance ★ ⚠ same type
CD14 p.Arg117Ser 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/cd14-p-val333ile (accessed [today's date]).

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