Is PHGDH p.Pro99Arg (c.296C>G) pathogenic?

PHGDH p.Pro99Arg (c.296C>G) is classified Benign/Likely benign in PHGDH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.9452); Rare (popmax 0.62%, amr); Associated with PHGDH deficiency.

What condition is associated with PHGDH p.Pro99Arg (c.296C>G)?

PHGDH p.Pro99Arg (c.296C>G) is associated with PHGDH deficiency, Neu-Laxova syndrome 1 (ClinVar).

How common is PHGDH p.Pro99Arg (c.296C>G) in the general population?

PHGDH p.Pro99Arg (c.296C>G) is rare (popmax 0.62%, amr) (gnomAD).

What do computational predictors say about PHGDH p.Pro99Arg (c.296C>G)?

AlphaMissense predicts likely pathogenic (score 0.9452) — an in-silico prediction, not a clinical call.

PHGDH p.Pro99Arg

c.296C>G · rs182600362 · VCV709534

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9452 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.62%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHGDH deficiency

Computational evidence

Protein change
AlphaMissense	0.9452	likely pathogenic
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -15.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 32 kb · p 0.037 · regional, not allelic
Overall
CADD	32.0	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 0.62% Admixed American · 372/60,006 alleles

Filtering AF 0.568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.548%

Overall 0.0246% 397/1,613,058 alleles · rare exomes 349/1,460,868 · genomes 48/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.62%	161
Remaining individualsnot grpmax-eligible	0.0208%	4,806
East Asian	0.0112%	8,966
South Asian	0.00549%	18,208
African / African-American	0.00133%	74,988
European (non-Finnish)	8.48e-05%	1,179,110

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: PHGDH
Protein: p.Pro99Arg
Coding: c.296C>G
MANE Select: NM_006623
dbSNP: rs182600362
Type: single nucleotide variant
Location: chr1:119723381 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06 · 21 PDB
Residue 99: an α-helix

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

Disease context

PHGDH deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Neu-Laxova syndrome 1

Similar variants

PHGDH c.1078+1G>A Likely pathogenic ★★ same condition
PHGDH c.138+1G>T Likely pathogenic ★★ same condition
PHGDH c.139-2A>G Likely pathogenic ★★ same condition
PHGDH c.290+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.357-1G>A Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.412-1G>C Likely pathogenic ★★ same condition
PHGDH c.643+1G>A Likely pathogenic ★★ same condition
PHGDH p.Arg135Trp Pathogenic/Likely pathogenic ★★ same condition

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/phgdh-p-pro99arg (accessed [today's date]).

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